USP22 Data Analysis

HGNC Gene Name: ubiquitin specific peptidase 22
HGNC Gene Symbol: USP22
Identifiers: hgnc:12621 NCBIGene:23326 uniprot:Q9UPT9
Orthologs: mgi:2144157 rgd:1310354
INDRA Statements: deubiquitinations all statements
Pathway Commons: Search for USP22
Number of Papers: 242 retrieved on 2023-02-19

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol	Name	DepMap Correlation	Evidence	CCLE Correlation	CCLE Z-score	CCLE p-value (adj)
SUPT20H	SPT20 homolog, SAGA complex component	0.542	BioGRID IntAct Pathway Commons INDRA (1) Reactome (3)	0.06	0.24	3.83e-01
TADA1	transcriptional adaptor 1	0.509	BioGRID IntAct INDRA (1) Reactome (3)	0.12	0.59	5.20e-02
TAF5L	TATA-box binding protein associated factor 5 like	0.496	BioGRID IntAct INDRA (1) Reactome (3)	0.11	0.50	8.95e-02
TADA2B	transcriptional adaptor 2B	0.472	BioGRID IntAct INDRA (1) Reactome (7)	0.19	0.95	2.41e-03
TAF6L	TATA-box binding protein associated factor 6 like	0.462	BioGRID IntAct INDRA (1) Reactome (3)	0.34	1.77	9.52e-10
TADA3	transcriptional adaptor 3	0.444	BioGRID IntAct INDRA (1) Reactome (7)	0.07	0.30	2.92e-01
ATXN7	ataxin 7	0.438	BioGRID INDRA (6) Reactome (7)	0.11	0.52	8.76e-02

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP22using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier	GO Name	GO Type	p-value	p-value (adj.)	q-value
GO:0070461	SAGA-type complex	Cellular Component	4.07e-17	3.70e-15	1.07e-15
GO:0030914	STAGA complex	Cellular Component	8.12e-16	7.38e-14	1.07e-14
GO:0031248	protein acetyltransferase complex	Cellular Component	8.77e-14	7.98e-12	7.69e-13
GO:0000124	SAGA complex	Cellular Component	8.84e-12	8.04e-10	5.81e-11
GO:0034212	peptide N-acetyltransferase activity	Molecular Function	1.64e-11	1.49e-09	8.64e-11
GO:0008080	N-acetyltransferase activity	Molecular Function	4.22e-11	3.84e-09	1.85e-10
GO:0016407	acetyltransferase activity	Molecular Function	1.13e-10	1.03e-08	3.90e-10
GO:0016410	N-acyltransferase activity	Molecular Function	1.19e-10	1.08e-08	3.90e-10
GO:0018394	peptidyl-lysine acetylation	Biological Process	9.99e-10	9.09e-08	2.92e-09
GO:0016569	covalent chromatin modification	Biological Process	1.48e-09	1.34e-07	3.89e-09
GO:0006473	protein acetylation	Biological Process	2.49e-09	2.27e-07	5.96e-09
GO:0043966	histone H3 acetylation	Biological Process	2.73e-09	2.49e-07	5.99e-09
GO:0043543	protein acylation	Biological Process	6.80e-09	6.19e-07	1.38e-08
GO:0016746	transferase activity, transferring acyl groups	Molecular Function	9.55e-09	8.69e-07	1.79e-08
GO:1905368	peptidase complex	Cellular Component	1.64e-08	1.49e-06	2.87e-08
GO:0003713	transcription coactivator activity	Molecular Function	2.58e-08	2.35e-06	4.24e-08
GO:0018205	peptidyl-lysine modification	Biological Process	7.26e-08	6.61e-06	1.12e-07
GO:0016591	RNA polymerase II, holoenzyme	Cellular Component	2.79e-06	2.54e-04	4.08e-06
GO:0030880	RNA polymerase complex	Cellular Component	6.70e-06	6.10e-04	9.29e-06
GO:0033276	transcription factor TFTC complex	Cellular Component	1.06e-05	9.64e-04	1.39e-05
GO:0061695	transferase complex, transferring phosphorus-containing groups	Cellular Component	8.16e-05	7.43e-03	9.34e-05
GO:0070646	protein modification by small protein removal	Biological Process	1.29e-04	1.18e-02	1.42e-04

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP22 using CRISPR-Cas9.

Knockout Differential Expression

Symbol	Name	log₂-fold-change	p-value	p-value (adj.)
USP22	ubiquitin specific peptidase 22	-1.60e+00	7.36e-14	1.62e-09
DNAJB1	DnaJ heat shock protein family (Hsp40) member B1	1.02e+00	9.34e-10	1.03e-05

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP22 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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USP22 deubiquitinates Histone_H2B. 10 / 14

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USP22 may deubiquitinate H2A and H2B, subunits of the hSAGA complex that activate transcription factors and promote carcinogenesis [XREF_BIBR].

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As we discussed previously, USP22 is a component of a transcriptional activator complex SAGA and can deubiquitinate histones H2A and H2B, as well as several other substrates (Zhang et al., 2008a, b).

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USP22 is a component of the SAGA transcriptional coactivator complex and can deubiquitinate H2A and H2B [XREF_BIBR - XREF_BIBR].

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USP22 deubiquitylates both, H2A and H2B.

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Remarkably, USP22, the human ortholog of Ubp8, forms a similar SAGA DUB module and deubiquitinates both H2A and H2B.

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USP22 is able to deubiquitinate histone H2A and H2B in vitro and is required for androgen receptor transcription activation.

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However, de-ubiquitylation of H2B by Usp22, the human homolog of yeast Ubp8, inhibits heterochromatic silencing and promotes gene activation [XREF_BIBR, XREF_BIBR].

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The requirement of ATXN7L3 for H2B deubiquitination by USP22, USP27x, and USP51 suggests that all three use the ATXN7L3 zinc finger to dock the H2A and H2B acidic patch in a manner similar to that shown in the structure of the yeast DUB module bound to ubiquitinated nucleosomes.

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USP22 was initially reported to promote deubiquitylation of histones H2A and H2B, leading to transcription activation.

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As a subunit of hSAGA, USP22 participates in the deubiquitination of histones H2A and H2B and the acetylation of histone H4 to regulate gene transcription and expression.

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USP22 deubiquitinates SIRT1. 9 / 9

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Ubiquitin specific protease 22 (USP22) reduced Sirt1 ubiquitination and degradation and decreased FN and TGF-beta1 expression in GMCs under both basal and AGEs treated conditions.

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For instance, HULC can upregulate the expression of the ubiquitin specific peptidase 22 (USP22) protein by suppressing miR-6825-5p, miR-6845-5p, and miR-6886-3p at the epigenetic or transcriptional level in HCC cells; USP22 enhances the HULC induced deubiquitination of Sirt1 and stabilizes it, and Sirt1 stability induces the autophagy of HCC cells, thus increasing the resistance of HCC cells to oxaliplatin [XREF_BIBR].

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In addition, USP22 knockdown prevented c-MYC-mediated reduction of SIRT1 ubiquitination (XREF_FIG) and increase in SIRT1 expression (XREF_SUPPLEMENTARY).

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Ubiquitin-specific peptidase USP22 negatively regulates the STAT signaling pathway by deubiquitinating SIRT1.

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USP22 can deubiquitinate and stabilize the expression of Sirt1.

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Collectively, USP22 might deubiquitinate SIRT1 and subsequently activate the AKT pathway, increasing the expression of MRP1 to induce MDR in HCC cells.

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Given that SIRT1 is deubiquitinated by USP22 and stabilized at the protein level (Armour etal., 2013; Lin etal., 2012) and previous studies have reported that SIRT1 could negatively influence the chemosensitivity of HCC cells (Chen etal., 2012), our results supported the notion that USP22 increases SIRT1 protein levels in HCC cells.

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USP22 can deubiquitinate Sirt1 and enhance its stability through c-MYC-related network, leading to FLT3 tyrosine kinase inhibitors (TKIs) resistance in acute myeloid leukemia (AML).

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USP22 deubiquitinates KDM1A. 7 / 7

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These results indicate that USP22 deubiquitinates and stabilizes KDM1A.

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Moreover, using in vitro deubiquitination assay, we found that KDM1A ubiquitination was decreased by incubating with recombinant USP22, suggesting that USP22 deubiquitinates KDM1A directly (XREF_FIG).

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In addition, deubiquitination of KDM1A by USP22 was attenuated after GSK3beta knockdown (XREF_FIG).

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USP22 deubiquitinated LSD1 in RB.

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However, of those four DUBs, only USP22 substantially decreased KDM1A ubiquitination (XREF_SUPPLEMENTARY).

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Furthermore, knockdown of USP22 in GSC11 cells increased KDM1A ubiquitination (XREF_FIG).

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USP22 deubiquitinates TERF1. 6 / 6

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For example, USP22 promotes TRF1 deubiquitylation to enhance TRF1 protein stability and maintain telomere integrity.

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Given the known regulation of TRF1 by ubiquitination, we hypothesized that the SAGA complex might facilitate Usp22 dependent deubiquitination of TRF1 and that loss of Gcn5 might alter this activity by compromising complex integrity.

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Additionally, Usp22 directly deubiquitinates TRF1 (TBP (TATA box binding protein)-related factor 1) to regulate the transcription of cell cycle and apoptosis genes [XREF_BIBR] and inhibits the transcriptional activity of p53 by deubiquitinating SIRT1 histone deacetylase [XREF_BIBR] and by regulating MDMX stability [XREF_BIBR].

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GCN5 and USP22 also protect telomeres from DNA damage response through the stabilization of a shelterin component called TRF1, and interestingly, this regulation is not transcriptional but involves USP22 mediated deubiquitination of TRF1 [XREF_BIBR].

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This dissociation leads to lowered USP22 activity, which in turn leads to increased ubiquitination and turnover of TRF1 (XREF_FIG).

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USP22 deubiquitinates CD274. 5 / 5

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However, our previous study demonstrated that USP22 induces the deubiquitination of PD-L1 and prevents PD-L1 degradation.

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USP22 can deubiquitinate PD-L1 itself or CSN5 for their stabilization [233] (Figure 3).

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USP22 deubiquitinated PD-L1 and inhibited its proteasome degradation.

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USP22 deubiquitinates CD274 to suppress anti-cancer immunity.

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Here, we identified ubiquitin-specific protease 22 (USP22) as a novel deubiquitinase of CD274.

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USP22 deubiquitinates Histone-H2A. 4 / 4

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USP22 was initially reported to promote deubiquitylation of histones H2A and H2B, leading to transcription activation.

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As a subunit of hSAGA, USP22 participates in the deubiquitination of histones H2A and H2B and the acetylation of histone H4 to regulate gene transcription and expression.

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Several DUBs have been implicated in histone deubiquitination, including USP3, USP12, USP22, and USP46, which deubiquitinate both histones H2A and histones H2B [XREF_BIBR].

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As we discussed previously, USP22 is a component of a transcriptional activator complex SAGA and can deubiquitinate histones H2A and H2B, as well as several other substrates (Zhang et al., 2008a, b).

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USP22 deubiquitinates CCNB1. 4 / 4

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Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1.

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Indeed, USP22 inhibited CCNB1 ubiquitination both in vivo and in vitro (XREF_FIG and XREF_SUPPLEMENTARY).

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The deubiquitinase catalytic activity of USP22 is required for CCNB1 deubiquitination because the catalytically inactive USP22 (USP22 and C185A) mutant failed to suppress CCNB1 ubiquitination without affecting its interaction with CCNB1 (XREF_SUPPLEMENTARY).

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USP22 deubiquitinates cyclin B1, stabilizes cyclin B1 by antagonizing proteasome mediated degradation, and promotes itaccumulation in the nucleus (Lin etal., 2015; Melo-Cardenas etal., 2016).

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USP22 deubiquitinates EGFR. 4 / 4

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Similarly, shRNA knockdown of USP22 resulted in accumulated Ubn-EGFR, which further confirmed that USP22 antagonizes EGFR ubiquitination.

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Mechanistically, USP22 deubiquitinates EGFR localized on late endosomes, prevents ubiquitination mediated EGFR degradation and enhances recycling of EGFR after EGF stimulation.

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Additionally, USP22 sustained the activation of multiple EGFR downstream signaling pathways, including STAT3, AKT/mTOR and MEK/ERK pathways, in lung ADC cell lines H1975 and PC9.

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In this model, late endosome localized USP22 deubiquitinates EGFR and impedes sorting of EGFR to the lysosome, thus sustaining the trafficking of EGFR to the plasma membrane (Figs. 6 and 9).

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USP22 deubiquitinates BMI1. 4 / 4

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USP22 interacts with and deubiquitinates BMI1 for post-translational stabilization.

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All these findings indicate USP22 as a novel deubiquitinase of BMI1 in glioma.

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3.3 USP22 deubiquitinates BMI1 for protein stabilization.

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To test whether the endogenous BMI1 is also deubiquitinated by USP22 in glioma cells, we knocked down endogenous USP22 in U251 cells pretreated with CHX and found that endogenous BMI1 also became unstable and degraded rapidly.

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USP22 deubiquitinates Histone. 4 / 4

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USP22 deubiquitylates histone and non histone substrates and has been associated with cancer progression and spinocerebellar ataxia.

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USP22 also deubiquitinates non histone proteins, including telomeric repeat binding factor 1 (TRF1), sirtuin 1 (SIRT1), cyclin B1 and others, leading to protein stabilization by preventing proteasome mediated degradation.

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USP22 deubiquitinates histone H2Bub and H2Aub.

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In addition, certain non histone proteins such as sirtuin 1 (Sirt1) and fructose-bisphosphatase 1 (FBP1) could be deubiquitinated by USP22.

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USP22 deubiquitinates MYC. 3 / 3

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It could be through a direct mechanism where USP22 deubiquitylates c-MYC inducing its stabilization and activation, or indirectly through ubiquitin removal from histones at c-MYC target genes, recruitment of other transcriptional machinery or deubiquitylation of proteins important for c-MYC activity.

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We found that USP22 promotes deubiquitination of c-Myc in several breast cancer cell lines, resulting in increased levels of c-Myc.

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USP22 leads to the deubiquitination of KPNA2. 2 / 2

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USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2.

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USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2.

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USP22 deubiquitinates NFATC2. 2 / 2

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Gao et al found that USP22 interacts with and deubiquitinates NFATc2, and also stabilizes NFATc2 protein and promotes NFATc2 function to facilitate IL-2 expression in T cells.

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USP22 deubiquitinates TBP. 1 / 1

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USP22 affects cell population proliferation

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USP22 activates cell population proliferation.

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USP22 activates cell population proliferation. 10 / 59

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USP22 knockdown significantly decreased in vitro survival, proliferation, migration, and invasiveness of GC cells compared with the controls.

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In previous studies, silencing of USP22 significantly inhibited tumor cell proliferation.

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By contrast, USP22 was overexpressed in NPC cells and promoted the proliferation of NPC.

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Knockdown of USP22 significantly inhibited the viability of CAL-62 and 8505C cells, and impaired proliferation as revealed by reduced EdU incorporation in CAL-62 and 8505C cells.

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Together, these data showed that USP22 silencing inhibited the proliferation of ATC cells in vitro.

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Silencing of USP22 downregulated COX-2, decreased its half-life, and inhibited lung carcinoma cell proliferation by directly interacting with and modulating the stability and activity of COX-2 through the regulation of its ubiquitination status.

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XREF_BIBR - XREF_BIBR Zhang and colleagues have demonstrated that ectopic overexpression of USP22 promotes cell proliferation and that suppression of USP22 expression by small hairpin RNA induces cell cycle arrest in human lung cancer cells.

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iv ) The downregulation of USP22 not only suppresses multidrug resistance-associated protein 1 ( MRP1 ) , enhances the intracellular accumulation of sorafenib , and finally inhibits cell proliferation and cancer angiogenesis , but also inhibits glycolysis in hepatocellular carcinoma ( HCC ) cells , enhancing sorafenib chemosensitivity and impairing cell metabolism .

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Previous studies showed that USP22 enhances cancer cell proliferation through interaction with Rb and p53.

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Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance related proteins (MDR1, LRP, MRP1).

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USP22 inhibits cell population proliferation.

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USP22 inhibits cell population proliferation. 10 / 30

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Together, these data showed that USP22 silencing inhibited the proliferation of ATC cells in vitro .

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Consistently, we demonstrated that USP22 silencing inhibited the proliferation of human ATC cells (8505C and CAL-62).

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A recent study suggested that USP22 could increase TGF-β expression and promote the epithelial–mesenchymal transition (EMT). xref In addition, another study demonstrated that silencing USP22 could inhibit proliferation and induce cell cycle arrest in bladder cancer cells. xref Furthermore, USP22 was also reported with high expression level in different malignancies, such as breast cancer xref and colorectal cancer. xref Thus, these lines of evidence strongly suggested that the oncogenic role of the USP22 might contribute to progression and predict the prognosis and become an attractive therapeutic target in cancers.

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The assay results showed that USP22 downregulation significantly inhibited the proliferation (XREF_FIG) and invasion (XREF_FIG) of U2OS and MG-63 cells.

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Additionally, investigation into the underlying mechanism, using small interfering RNA, revealed that the downregulation of USP22 inhibited proliferation and promoted apoptosis though the phosphoinositide 3-kinase/protein kinase B signaling pathway.

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USP22 depletion inhibits the proliferation of ATC cells in vitro.

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USP22 Silencing Inhibits Proliferation and Induces Apoptosis and Cell Cycle Arrest in NSCLC Cells.

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Depletion of USP22 suppressed cell proliferation in vitro and tumor growth in vivo.

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USP22 silencing inhibits GC cells proliferation.

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Downregulation of USP22 Inhibited OS Cell Proliferation and Invasion In Vitro.

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USP22 affects apoptotic process

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USP22 inhibits apoptotic process.

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USP22 inhibits apoptotic process. 10 / 39

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USP22 Silencing Inhibits Proliferation and Induces Apoptosis and Cell Cycle Arrest in NSCLC Cells.

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After treating with 1.25 μmol/L oxaliplatin for 48 h, USP22 overexpression can inhibit SW480 cells apoptosis.

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USP22 knockdown promotes apoptosis of ATC cells in vitro.

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RNA interference mediated USP22 gene silencing promotes human brain glioma apoptosis and induces cell cycle arrest.

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As a novel de-ubiquitinating enzyme with ubiquitin hydrolase activity, USP22 might inhibit apoptosis in HCC by activating the BMI-1-mediated PcG stem cell pathway [ xref ].

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Silencing of USP22 promotes human retinoblastoma cell apoptosis by inhibiting TERT and P53 pathway 36.

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In retinoblastoma, the depletion of USP22 has been shown to induce cancer cell apoptosis by suppressing the TERT/P53 signal pathway .

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As a consequence, gain of USP22 functions promotes cell cycle progression and inhibits cell apoptosis, leading to cancer cell hyper-proliferation and tumorigenesis.

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In the attempt to explore the mechanisms by which USP22 silencing leads to ATC cell apoptosis, we found that the proapoptotic members of Bcl-2 family proteins, Bid and Bax, were upregulated in response to USP22 knockdown, consistent with increased activation of caspase-3.

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Our previous studies have confirmed that defects in USP22 can not only cause cell cycle arrest in G0/G1 phase, but also inhibit apoptosis and promote tumor cell proliferation [XREF_BIBR].

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Modified USP22 inhibits apoptotic process. 1 / 1

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Further experimental verification showed that overexpression of USP22 reversed the suppression effects of miR-132-3p overexpression on the proliferation, migration and invasion of SW480 and SW620 cells, as well as the acceleration effect of apoptosis (XREF_FIG -G), further confirming that miR-132-3p regulated the progression of CRC by targeting USP22.

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USP22 activates apoptotic process.

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USP22 activates apoptotic process. 8 / 10

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Silencing of USP22 in podocytes attenuated high d-glucose-induced apoptosis and inflammatory responses, evidenced by increases in proliferation and MMP levels and decreases in the apoptotic rate, ROS production, the Bax and Bcl -2 ratio, caspase-3 expression and secretion of TNF-alpha, IL-1beta, IL-6 and TGF-beta1.

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Both elevated exosomal miR-let-7a or silenced USP22 reduced the apoptosis of renal cells and improved kidney function.

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Moreover, USP22 down-regulation in HUVECs led to decreased proliferation, angiogenesis, vasodilation, apoptosis, and systolic function.

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USP22 depletion could significantly inhibit the proliferation and invasion, and promote the apoptosis of ATC cells in vitro.

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Further analysis demonstrated that USP22 downregulation activated mitochondrial apoptosis by regulating several apoptosis related proteins, including Bcl-2, Bax, cytochrome c and caspase-3.

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Down-regulation of USP22 expression by siRNA induces the mitochondrial apoptosis of HCC cells.

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To investigate the molecular mechanism underlying USP22 silencing induced ATC cell apoptosis, we examined the cellular levels of documented apoptosis regulators or executioners.

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Modified USP22 activates apoptotic process. 1 / 1

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The overexpression of USP22 significantly enhanced cell proliferation potency and telomerase activity, elevated TERT expression level, inhibited p53 expression and cell aging, as well as decreased cell apoptosis or DNA damage.

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USP22 affects Neoplasm Invasiveness

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USP22 activates Neoplasm Invasiveness.

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USP22 activates Neoplasm Invasiveness. 10 / 28

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These results suggest that while USP22 promotes cell migration and invasion, loss of USP22 sensitizes EGFR mutant NSCLC cells to erlotinib in vitro.

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In lung adenocarcinoma cells, USP22 was implicated to promote cell invasion by the induction of EMT.

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USP22 and STAT3 co-depletion partly rescued the MMP9 proteolytic activity and invasion of SW480 cells, compared with that of STAT3 depletion alone.

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USP22 can promote lung cancer cell invasion via epithelial-mesenchymal transition (EMT), which participates in the metastasis of primary tumors by activating TGF-beta1 [XREF_BIBR].

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We drew a conclusion that USP22 could increase the abilities of proliferation, migration and invasion of glioma cells, and promote the growth and development of glioma.

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Through measuring the proliferation, migration and invasion of SW480 and SW620 cells, we uncovered that USP22 knockdown could suppress the proliferation, migration and invasion of CRC cells, while USP22 overexpression had an opposite effect (Supplement Figure 2).

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These results indicate that USP22 increases CRC cell migration and invasion abilities by promoting EMT.

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Silencing USP22 decreased the migration and invasion of Bel/Fu cells, and combination with 5-Fu further decreased the rate of migration and number of invading cells.

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Taken together, these results indicate that USP22 increases cell migration and invasion by inducing EMT by binding to the promoter of AP4 to activate its transcription.

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We report that deletion of USP22 in pancreatic tumor cells reduced the infiltration of myeloid cells and promoted the infiltration of T cells and NK cells, leading to an improved response to combination immunotherapy.

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Ablation of USP22 in liver tumor cells has been shown to increase tumor immunogenicity and promote infiltration of T cells into the resulting liver tumors.

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USP22 inhibits Neoplasm Invasiveness.

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USP22 downregulation inhibited OS cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro.

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In conclusion, USP22 attenuated the invasion capacity of colon cancer cells by inhibiting the STAT3 and MMP9 signaling pathway.

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In colon cancer, USP22 was reported to attenuate the invasion capacity of colon cancer cells by inhibiting the STAT3 and MMP9 signaling pathway.

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Downregulation of USP22 inhibited OS cell proliferation, invasion, and EMT in vitro.

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Downregulation of USP22 inhibited OS cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) in vitro.

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Downregulation of USP22 Inhibited OS Cell Proliferation and Invasion In Vitro.

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The results of in vitro and in vivo studies confirmed USP22 depletion reduced the growth and invasion of ATC cells by regulating the expression and activation of a series of pro tumorigenesis molecules.

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We also suggested that downregulation of USP22 inhibited OS cell proliferation and invasion in vitro.

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USP22 depletion could significantly inhibit the proliferation and invasion, and promote the apoptosis of ATC cells in vitro.

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The assay results showed that USP22 downregulation significantly inhibited the proliferation (XREF_FIG) and invasion (XREF_FIG) of U2OS and MG-63 cells.

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Modified USP22 inhibits Neoplasm Invasiveness. 1 / 1

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USP22 affects AR

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USP22 activates AR.

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USP22 activates AR. 10 / 25

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Given the ability of USP22 to enhance AR accumulation, AR activity, and CRPC, the biological impact of a model of tetracycline inducible shUSP22 was developed in therapy sensitive PCa cells.

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Together, these data demonstrate that USP22 regulates ligand independent AR residence at target gene loci and promotes AR driven CRPC gene profiles, which may have specificity for USP22 perturbation, further implicating USP22 as an independent effector of aggressive tumor phenotypes.

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These data demonstrate that USP22 potentiates both ligand dependent and ligand independent AR function.

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In addition, USP22 expression was shown to increase the abundance of c-Myc and the androgen receptor itself [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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These data suggest that USP22 functions to enhance AR stability and promote inappropriate castration resistant AR signaling through proteasome dependent regulation of AR levels.

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Moreover, USP22 and DHT acted cooperatively to further enhance AR activity (XREF_FIG).

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Strikingly, USP22 deregulation significantly increased AR occupancy at known ARORs (1.15-2.6% input; XREF_FIG), but not in control regions of the KLK3 and PSA (' EF ' region, XREF_SUPPLEMENTARY).

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Based on the data above, suppression of USP22 in models of ADT sensitive PCa and aggressive CRPC decreased the AR signaling axis (XREF_FIG and XREF_FIG).

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USP22 Enhances AR Activity and Promotes Bypass of AR Antagonists.

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By contrast, USP22 deregulation induced marked enhancement of ligand independent AR activity, determined by analyses of multiple, clinically relevant AR target genes (XREF_FIG).

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USP22 inhibits AR.

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As shown, in CRPC cells, USP22 depletion suppressed AR protein accumulation in both the androgen stimulated and deprived conditions (XREF_FIG, compare lanes 1,2 and 3,4).

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First, depletion of USP22 significantly reduced AR protein (~ 73%) compared to control (XREF_FIG, compare lanes 3,4 and 7,8).

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Additionally, in both culture conditions, USP22 depletion diminished AR activity (XREF_FIG).

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In androgen deprived conditions, USP22 depletion modestly decreased basal AR activity.

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USP22 decreases the amount of AR.

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USP22 Depletion Suppresses Ligand Dependent and Castration Resistant AR Expression and Activity.

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Conversely, depletion of USP22 dramatically down-regulates AR protein levels and abrogates basal and DHT stimulated AR activity in both ADT sensitive and CRPC cells.

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In contrast, USP22 depletion reduced AR protein levels in the absence of androgen, and inhibited DHT induced AR expression, within in models of therapy sensitive disease (XREF_FIG, compare lanes 2, 4).

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Schrecengost et al XREF_BIBR previously showed that USP22 depletion dramatically downregulated androgen receptor protein levels and abolished androgen receptor activity in both androgen deprivation therapy and castration resistant prostate adenocarcinoma cells.

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USP22 increases the amount of AR.

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The observations that USP22 upregulation is sufficient to promote ligand independent AR expression and activity, and induce Casodex resistance are clinically relevant, as these attributes reflect key biochemical characteristics of CRPC.

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Further, USP22 mediates AR expression through a proteasome dependent mechanism, since modeling clinically-relevant USP22 upregulation results in an increased AR protein half-life and proteasome inhibition rescued the decreased AR expression following USP22 depletion.

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USP22 affects cell cycle

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USP22 activates cell cycle.

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Studies have shown that overexpression of USP22 can enhance the inhibitory effect of cell cycle inhibitors such as p21 and enhance the proliferation of tumor cells, thus promoting the occurrence and development of tumors [XREF_BIBR].

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Knock-down of USP22 by small interfering RNA interference inhibits HepG2 cell proliferation and induces cell cycle arrest.

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We found that inhibition of USP22 suppressed cell proliferation by inducing G1 phase cell cycle arrest through synergy with oncogenic transforming growth factor-beta1 (TGFB1).

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Gain- and loss-of-function assays showed that USP22 promoted gastric cancer cell growth and cell cycle transition while suppressing apoptosis in vitro.

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Therefore, reduced USP22 expression can not systematically induce cell cycle arrest and hinder cancer progression, as suggested above.

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XREF_BIBR In addition, another study demonstrated that silencing USP22 could inhibit proliferation and induce cell cycle arrest in bladder cancer cells.

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Our group first demonstrated that knockdown of USP22 induces cell cycle arrest and inhibits cell growth in the HCC cell line HepG2 [ 8] .

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USP22 Modulates Cell Cycle Progression.

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First, using hormone-proficient conditions, USP22 enhanced the rate of cell cycle progression, evidenced through increased BrdU incorporation (XREF_FIG, left).

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While it is clear that USP22 is overexpressed in various cancer types and may promote oncogenesis by altering gene expression, cell death and cell cycle progression, emerging evidence suggests that USP22 also harbors tumor suppressor like properties.

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USP22 inhibits cell cycle.

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Importantly, overexpression of MDMX reversed USP22 silencing, induced p53 activation, growth inhibition, cell cycle arrest and apoptosis in A549 cells (XREF_FIG B-E).

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As shown, doxycycline (Dox) decreased USP22, resulting in marked loss of AR (XREF_FIG, top), attenuated cell cycle progression (determined by BrdU incorporation XREF_FIG, top right, middle), and significantly suppressed of cell doubling (XREF_FIG, bottom).

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Also, USP22 silencing promotes apoptosis and cell cycle arrest in human brain gliomas.

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Knockdown of USP22 was found to suppress cell proliferation in vitro and tumour growth in vivo by inducing G1 phase cell cycle arrest through synergy with TGF-beta1 (Ji et al., 2015).

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However, Ling et al reported that knockdown of USP22 by siRNA induced cells G0/G1 cell cycle arrest via the c-Myc and cyclin D2 pathway in HepG2 cells.

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RNA interference mediated USP22 gene silencing promotes human brain glioma apoptosis and induces cell cycle arrest.

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Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others.

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USP22 Silencing Inhibits Proliferation and Induces Apoptosis and Cell Cycle Arrest in NSCLC Cells.

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The USP22 silencing both in CNE-1 and CNE-2 cells caused them to accumulate in the G0/G1 phase of the cell cycle.

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USP22 affects Neoplasm Metastasis

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In stomach cancer, USP22 abundance increased from normal tissue to primary carcinoma to lymph node metastasis and was also associated with shorter patient survival (26 vs. 59 months disease specific survival for USP22 positive vs. -negative primary carcinoma) [XREF_BIBR].

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These findings suggest that AP4 may be involved in USP22 driven CRC progression and metastasis.

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Oncogenic USP22 supports gastric cancer growth and metastasis by activating c-Myc/NAMPT/SIRT1-dependent FOXO1 and YAP signaling.

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USP22 may promote tumor progression and metastasis.

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We found that the USP22 expression increased significantly from normal mucosa to carcinomas and from carcinomas to lymph node metastasis.

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In addition , downregulation of USP22 suppressed OS tumor growth and metastasis in vivo .

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As expected , downregulation of USP22 suppressed OS tumor growth and metastasis in vivo .

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These results suggest that USP22 promotes tumor development and metastasis, and highlight USP22 as a novel prognostic marker and potential therapeutic target in ATC.

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These findings indicate that USP22 promotes CRC invasion and metastasis by inducing EMT via AP4 activation.

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These results lend further support to the results of our vitro experimental studies, as they showed that USP22 promotes CRC cell metastasis by activating AP4 to induce EMT.

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USP22 inhibits Neoplasm Metastasis.

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We also showed that ablation of tumor cell-intrinsic USP22 suppressed metastasis of pancreatic tumor cells in a T cell dependent manner.

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Consistent with in vitro findings, downregulation of USP22 in ATC cells impeded tumor growth and lung metastasis in vivo.

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Moreover, USP22 overexpression can promote EMT and TGF-beta expression, whereas depletion of USP22 can reverse EMT and reduce metastasis of lung adenocarcinomas.

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XREF_BIBR Downregulation of USP22 has been shown to suppress osteosarcoma growth and metastasis through PI3K and Akt pathway.

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These results suggest that USP22 downregulation inhibited OS tumor growth and metastasis in vivo.

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Downregulation of USP22 Inhibited OS Tumor Growth and Metastasis In Vivo.

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In addition, downregulation of USP22 suppressed OS tumor growth and metastasis in vivo.

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Similarly, Zhao et al. reported that USP22 depletion suppressed cell survival and proliferation as well as tumor growth and lung metastasis of anaplastic thyroid carcinoma cells XREF_BIBR.

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Collectively, these results suggested that USP22 depletion attenuates tumor growth and metastasis of ATC.

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As expected, downregulation of USP22 suppressed OS tumor growth and metastasis in vivo.

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USP22 affects cell growth

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Second, USP22 significantly increased cell growth in the presence of androgen (XREF_FIG, right).

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Our results demonstrated that USP22 silencing suppressed cell growth and induced cell apoptosis.

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Moreover, it has been shown that USP22 promotes cell growth by regulating the far upstream element (FUSE)-binding protein 1 (FBP1), a transcriptional regulator of p21 [XREF_BIBR].

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USP22 promotes cell growth even under hypoxia condition and with the treatment of ERalpha antagonist in breast cancer cells.

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Finally, we discover that USP22 knockdown leads to slower cell growth and reduced tumor size.

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USP22 Promotes Ligand dependent and Castrate resistant PCa Cell Growth.

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Collectively, our results show that USP22 silencing in HepG2 cells suppressed cell growth through mitochondrial apoptosis and that this suppression was dependent on caspase activation.

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Our data showed that USP22 silencing led to significantly slower cell growth compared with the control (p < 0.01 after 120 h) (XREF_FIG B).

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Knockdown of USP22 significantly retarded cell growth in H1975 cells compared to control (p < 0.05, Fig. 2 A), whereas overexpression of USP22 in PC9 cells accelerated cell growth (p < 0.01, Fig. 2 A)[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Taken together, our results suggest that USP22 promotes NSCLC cell growth in vitro and NSCLC tumorigenesis in vivo, and these effects are through MDMX up-regulation and subsequent p53 inhibition.

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These observations indicate that USP22 gene silencing by RNA interference inhibits HCC cell growth (Fig. xref ).

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Hence, we determined whether downregulation of USP22 suppresses colon cancer cell growth and cancer progression.

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USP22 siRNA suppressed cell growth.

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Furthermore, USP22 small interfering RNA inhibited cell growth and reduced the expression levels of Aurora-B, Survivin and Cyclin B, together with the upregulation of cyclin dependent kinase inhibitor 1A (p21).

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These results suggested that USP22 siRNA effectively inhibited OSCC cell growth in vitro.

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USP22 affects epithelial to mesenchymal transition

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USP22 activates epithelial to mesenchymal transition.

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These results suggested that overexpression USP22 induced EMT in lung adenocarcinoma cells.Moreover it is well known that TGF-beta1 stimulates the EMT in lung cancer cells [43].

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Previous studies have also shown that USP22 can promote tumor progression and induce EMT in various tumors [ 13 , 23 ] .

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Subsequent experiments showed that USP22 knockdown resulting from up-regulation of miR-30e-5p could inhibit proliferation, invasion, migration, and EMT in 5-8F cells.

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A more recently published report indicates that USP22 may promote tumor progression and induce EMT in colorectal carcinoma patients [ 13 ] .

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These findings indicate that USP22 promotes CRC invasion and metastasis by inducing EMT via AP4 activation.

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Moreover, we evaluated whether USP22 could induce EMT in cultured lung cancer cells.

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USP22 increases CRC cell migration and invasion by inducing EMT.

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In addition, we present evidence that USP22 promotes Bel/Fu cell growth, migration, invasion, EMT and chemoresistance.

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According to the results of previous studies, USP22 can induce EMT by regulating TGF-beta1 in lung cancer cells [XREF_BIBR], and elevated USP22 expression can promote EMT by up-regulating ZEB1 and Snail in pancreatic cancer cells though a process that involves focal adhesion kinase (FAK) signaling [XREF_BIBR].

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In vitro study revealed that USP22 can regulate proliferation and invasive properties, and induce EMT of lung adenocarcinoma cells.

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Moreover, USP22 overexpression can promote EMT and TGF-beta expression, whereas depletion of USP22 can reverse EMT and reduce metastasis of lung adenocarcinomas.

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Downregulation of USP22 inhibited OS cell proliferation, invasion, and EMT in vitro.

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The results suggested that USP22 downregulation obviously suppressed the EMT process in OS cells.

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USP22 affects SIRT1

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USP22 inhibits SIRT1.

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USP22 depletion enhanced Sirt1 degradation and displayed combined effects with AGEs to further promote FN and TGF-beta1 expression.

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USP22 Inhibits SIRT1 to Regulate Ferroptosis-Induced Cardiomyocyte Death.

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USP22 Inhibits SIRT1 to Regulate Ferroptosis-Induced Cardiomyocyte Death A previous study has shown that USP22 possesses the ability to stabilize SIRT1 by the process of deubiquitination ( Lin et al ., 2012 ) .

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Moreover, we found that USP22 inhibited the SIRT1 gene to regulate ferroptosis-induced cardiomyocyte death.

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Additionally, SIRT1 instability caused by loss of USP22, a deubiquitinating enzyme that stabilizes SIRT1, is associated with the defective embryogenesis in USP22 null mice [XREF_BIBR].

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USP22 knockdown reduced SIRT1 expression in FLT3-ITD AML cells, whereas USP22 overexpression increased SIRT1 levels by increasing protein stability, indicating that USP22 is an important positive regulator of SIRT1 in FLT3-ITD cells.

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USP22 upregulated Sirt1 expression by inhibiting its ubiquitin mediated degradation.

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In addition, USP22 knockdown prevented c-MYC-mediated reduction of SIRT1 ubiquitination (XREF_FIG) and increase in SIRT1 expression (XREF_SUPPLEMENTARY).

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Ectopic USP22 expression increased SIRT1 protein levels (XREF_FIG) without significantly affecting SIRT1 mRNA level (data not shown).

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In this study, USP22 directly interacted with SIRT1 and positively regulated SIRT1 protein expression.

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USP22 decreases the amount of SIRT1.

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In addition, USP22 could also decrease the acetylation of Ku70 by stabilizing the expression of Sirt1, thus inhibiting Bax mediated apoptosis and contributing to cisplatin resistance.

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Knockdown of endogenous USP22 in MV4-11 cells decreased SIRT1 protein levels (XREF_FIG) and significantly reduced cell growth (XREF_SUPPLEMENTARY).

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USP22 activates SIRT1.

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USP22 also increases SIRT1 protein stability, which leads to the suppression of p53 transcriptional activity and inhibition of cell death [XREF_BIBR, XREF_BIBR].

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USP22 affects TP53

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As for Myc, USP22 depletion blocked the ability of p53 to activate the transcription of its targets.

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In retinoblastoma, the depletion of USP22 has been shown to induce cancer cell apoptosis by suppressing the TERT/P53 signal pathway .

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Intriguingly, we found that USP22 silencing activates the p53 pathway in human NSCLC cells and tumor tissues along with downregulation of MDMX protein, a major negative regulator of p53.

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USP22 Silencing Down-Regulates MDMX and Up-Regulates the p53 Pathway in NSCLC Cells.

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Importantly, overexpression of MDMX reversed USP22 silencing, induced p53 activation, growth inhibition, cell cycle arrest and apoptosis in A549 cells (XREF_FIG B-E).

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Several studies demonstrated that USP22 silencing could activate p53.

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It has been reported that USP22 antagonizes p53 in bladder cancer cells through up-regulating MDM2 [XREF_BIBR].

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On the bases of these results, we speculated that USP22 silencing activates the p53 pathway in NSCLC cells by post-transcriptional down-regulation of MDMX.

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USP22 may antagonize p53 through Sirt1 stabilization to suppress cell apoptosis under DNA damage and during embryonic development (Lin etal., 2012).

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Hence USP22 silencing reduces the capacity of FBP1 to repress p21 (independently of TP53 status), which in turn inhibits CDKs to prevent the G1/S transition and resulting in G1 accumulation [XREF_BIBR].

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USP22 activates TP53.

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Several studies demonstrated that USP22 silencing could activate p53. xref , xref Because USP22, Ube2d4, and Ube3b were important downstream genes of YWHAZ, we infer that YWHAZ downregulates p53 by activating USP22, Ube2d4, and Ube3b, which make P53 ubiquitination and lead to its proteasomal degradation.

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USP22 promotes hypoxia induced hepatocellular carcinoma stemness by a HIF1alpha and USP22 positive feedback loop upon TP53 inactivation.

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Silencing of USP22 promotes human retinoblastoma cell apoptosis by inhibiting TERT and P53 pathway 36.

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USP22 Induces Cisplatin Resistance in Lung Adenocarcinoma by Regulating gammaH2AX Mediated DNA Damage Repair and Ku70 and Bax Mediated Apoptosis.

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According to that model, USP22 enhances DNA damage repair and cisplatin resistance by deubiquitinating histone H2A, which in turn facilitates the phosphorylation of histone H2AX.

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Combining with our previous results, we concluded that both USP22 and Sirt1 can induce cisplatin resistance, but Sirt1 overexpression ca n't phenocopy USP22 mediated cisplatin resistance.

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The study reveal the dual mechanism of USP22 involvement in cisplatin resistance : (1) USP22 enhances DNA damage repair and induce cisplatin resistance by promoting the phosphorylation of histone H2AX via deubiquitinating histone H2A.

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These results confirm that USP22 is involved in the cisplatin resistance of A549 and CDDP cells and H2AX, gammaH2AX, and Sirt1 may be responsible for USP22 mediated cisplatin resistance.

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To verify whether inhibition of USP22 expression could reverse the cisplatin resistance of A549 and CDDP cells, CCK8 assays showed that, after the inhibition of USP22 expression, the 48h IC50 of A549 and CDDP decreased from 0.925 +/- 0.04 muM to 0.337 +/- 0.03 muM.

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Moreover, the resistance degree of USP22 mediated cisplatin resistance was higher than Sirt1 mediated cisplatin resistance.

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To further confirm that USP22 induces cisplatin resistance via Sirt1, we added flow cytometric analysis results.

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USP22 inhibits cisplatin.

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In addition, the cisplatin sensitivity in cisplatin resistant A549 and CDDP cells was restored by USP22 inhibition in vivo and vitro.

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The cisplatin sensitivity in cisplatin resistant A549 and CDDP cells was restored by USP22 inhibition in vivo and vitro.

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The Cisplatin Sensitivity in Cisplatin Resistant A549 and CDDP Cells Was Restored by USP22 Inhibition.

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These results indicate that the cisplatin sensitivity in cisplatin resistant A549 and CDDP cells was restored by USP22 inhibition.

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These results suggest that inhibiting USP22 expression enhanced cisplatin sensitivity in lung adenocarcinoma by downregulation of Sirt1 and gammaH2AX in vivo.

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Furthermore, USP22 knockout significantly impaired non homologous DNA damage repair capacity, enhanced cisplatin and irradiation induced apoptosis in these cells.

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Inhibiting USP22 Expression Enhanced Cisplatin Sensitivity in Cisplatin Resistant A549 and CDDP Cell Nude Mouse Xenografts.

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USP22 affects AKT

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USP22 activates AKT.

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XREF_FIG A, knockdown of USP22 by shRNA inhibited the AKT and MRP1 pathway compared with control shRNA cells and wild-type cells.

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Previous study also showed that USP22 promotes cell cycle progression by positively regulating the PI3K and Akt pathway [XREF_BIBR].

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Western blot analysis showed that USP22 overexpression also induced activation of the RAS and ERK and PI3K and AKT pathways in SGC7901 cells and xenograft tumor tissues.

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Previous studies have confirmed that USP22 can promote the biological process of NSCLC cells by regulating BMI-1 and AKT signaling pathway [XREF_BIBR].

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Moreover, SIRT1 deficiency attenuated USP22 induced activation of the AKT and MRP1 pathway in BEL7402 cells, suggesting that USP22 regulated the AKT and MRP1 pathway in a SIRT1 dependent manner.

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These results suggest that USP22 downregulation inhibits OS cells by suppressing the PI3K and Akt pathway.

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We observed that USP22 could positively regulate the AKT pathway in a SIRT1 dependent manner.

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Similarly, overexpression of USP22 in BEL/7402 cells activated the AKT and MRP1 pathway.

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3.5 USP22 activates the AKT and MRP1 pathway depending on SIRT1 in HCC cells.

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USP22 inhibits AKT.

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Furthermore, our results showed that USP22 deletion also caused down-regulation of Akt and GSK3beta activity, which can also contribute to the reduction of cyclin D2.

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USP22 activates ABCC1. 9 / 9

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3.5 USP22 activates the AKT and MRP1 pathway depending on SIRT1 in HCC cells.

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XREF_FIG A, knockdown of USP22 by shRNA inhibited the AKT and MRP1 pathway compared with control shRNA cells and wild-type cells.

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The downregulation of USP22 suppresses multidrug resistance-associated protein 1 ( MRP1 ) to induce intracellular sorafenib accumulation and hampers glycolysis of HCC cells .

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] Our study provided strong evidence that the downregulation of USP22 by Gal-SLPs suppressed the expression of MRP1 and caused high intracellular sorafenib accumulation .

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] Downregulation of USP22 could inhibit the AKT / GSK-3beta pathway and further suppress the expression of MRP1 ( Figure 4a [ .

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In our previous study , USP22 bound to SIRT1 and subsequently activated the AKT pathway , increasing the expression of MRP1 to induce 5-FU resistance in HCC cells [ 15 ] .

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Similarly, overexpression of USP22 in BEL/7402 cells activated the AKT and MRP1 pathway.

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Both of these findings indicated that USP22 upregulated MRP1 depending on the AKT pathway.

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USP22 increases the amount of ABCC1.

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USP22 increases the amount of ABCC1. 3 / 3

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LY294002 (10mum) also suppressed USP22 induced high expression of MRP1 via inhibition of AKT pathway in BEL7402 cells.

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USP22 activates MYC. 10 / 13

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Furthermore, overexpression of USP22 stimulates breast cancer cell growth and colony formation, and increases c-Myc tumorigenic activity.

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Studies herein suggest that USP22 mediated MYC regulation in PCa is likely gene selective, based on USP22 increasing gene expression of AR/MYC co-regulated target (ODC) but not of multiple MYC targets.

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While these outcomes could occur via USP22 mediated MYC and CyclinD2 and/or BMI-1-mediated modulation, AR activity promotes tumorigenesis in several of these tumor types, including bladder, HCC and breast carcinoma.

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USP22 increased c-Myc stability via deubiquitination in breast cancer cells.

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Evidently, HnRNPA1 is a downstream transcription regulator of c-Myc (proto-oncogene) whereas USP22 positively regulates c-Myc stability and promotes tumorigenesis [XREF_BIBR, XREF_BIBR].

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C-Myc abundance is also indirectly increased by the activity of USP22 on its substrate SIRT1, a NAD dependent protein deacetylase [XREF_BIBR] (see Section 7), but this is not observed in all cell types [XREF_BIBR].

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Decreased levels of USP22 reduce the ability of c-MYC, which can stimulate activation of AP4 to directly or indirectly induce EMT [XREF_BIBR], activating the transcription of its targets [XREF_BIBR, XREF_BIBR].

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Deubiquitinating enzyme USP22 positively regulates c-Myc stability and tumorigenic activity in mammalian and breast cancer cells.

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In addition, USP22 expression was shown to increase the abundance of c-Myc and the androgen receptor itself [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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In conclusion, the present study reveals that USP22 in breast cancer cell lines increases c-Myc stability through c-Myc deubiquitination, which is closely correlated with breast cancer progression.

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USP22 inhibits MYC.

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USP22 inhibits MYC. 1 / 1

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Because the Myc protein controls the expression of thousands of other genes, the depletion of cellular USP22 can inhibit Myc function, inhibiting the invasive growth of cancer cells.

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USP22 affects BMI1

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USP22 increases the amount of BMI1.

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USP22 increases the amount of BMI1. 6 / 6

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Above, we demonstrated that USP22 silencing predominantly decreases the BMI1 protein levels rather than mRNA expression, and further alters GC cell proliferation, gastric CSC formation and maintenance of stem cell stemness, indicating post-transcriptional regulation of BMI1.

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Our results showed that USP22 silencing significantly down-regulated BMI1 protein expression and further affected gastric CSC self-renewal.

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We found USP22 silencing led to decreased expression of BMI1, as well as decreased P21 levels.

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We have reported that USP22 mediates cell survival and proliferation by promoting the expression of BMI-1 and upregulation of activated AKT pathway in colon cancer cells.

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USP22 knockdown remarkably decreased BMI1 protein level, but it barely affected BMI1 mRNA level in glioma cell lines.

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USP22 knockdown inhibits glioma stemness partially by downregulating the protein level but not the transcriptional level of BMI1.

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USP22 activates BMI1.

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USP22 activates BMI1. 6 / 6

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USP22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 protein.

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An in vitro study showed that the upregulation of USP22 mediated the enhanced expression of BMI1 and Cyclin D2, and was responsible for increased cell proliferation and the metastatic behavior of colon cancer cells .

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Moreover, WT-USP22 prolonged GFP-BMI1 half-life compared with that in cells transfected with control vector or CI-USP22.

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In this study, we demonstrated that USP22 mediated protein stabilization of BMI1 promotes gastric CSC stemness maintenance and GC progression, thereby providing a rationale for USP22 targeting as a potential therapeutic approach against GC.

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Additionally, USP22 silencing led to down-regulated BMI1.

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USP22 decreases the amount of CDKN1A. 9 / 9

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GSK3beta- and USP22 dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repressing BMP2, CDKN1A and GATA6 transcription, which results in cancer stem cell self-renewal and glioblastoma tumorigenesis.

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In MGC-803 cells and SGC-7901 cells, knockdown of USP22 and BMI1 both increased P21 expression and reduced the expression of CSC stemness genes of CD133 and SOX2.

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USP22 also suppresses CDKN1A and p21 -locus expression by deubiquitinating its transcriptional repressor FBP1 (Atanassov and Dent, 2011), and acts as a negative regulator of the tumor suppressor p53 b[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP22 has also been demonstrated to inhibit transcription of the p21 gene by deubiquitinating the transcriptional regulator, FBP1, leading to cell proliferation and tumorigenesis.

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USP22-mediated deubiquitination of PTEN inhibits pancreatic cancer progression by inducing p21 expression.

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Furthermore, our results showed that USP22 deletion caused down -- regulation of cyclin D2 expression and up -- regulation of p15 and p21 expression.

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We found that USP22 depletion inhibited the proliferation of the human GC cell lines MGC-803 and SGC-7901 cells and increased expression of P21, indicating cell cycle arrest [XREF_BIBR].

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Recent studies have demonstrated that USP22 can inhibit the transcription of the p21 gene by de-ubiquitinating the transcriptional regulator FBP1, leading to cell proliferation and tumorigenesis [XREF_BIBR].

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USP22 inhibits CDKN1A.

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USP22 inhibits CDKN1A. 2 / 2

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USP22 knockdown, using lentivirus delivered siRNA, increased the expression levels of cell cycle proteins P21 and P27, but reduced the levels of phosphorylated retinoblastoma protein, resulting in the inhibition of FaDu cell growth and proliferation.

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USP22 increases the amount of CDKN1A.

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USP22 increases the amount of CDKN1A. 2 / 2

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We found USP22 silencing led to decreased expression of BMI1, as well as decreased P21 levels.

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USP22 also play roles in cell cycle regulation, where depletion of USP22 increases the expression of p53 and p21, inhibits proliferation, and induces cell cycle arrest at G1 phase.

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USP22 affects TGFB1

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USP22 increases the amount of TGFB1.

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USP22 increases the amount of TGFB1. 4 / 5

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Ubiquitin specific protease 22 (USP22) reduces the degradation of sirtuin-1 and the expression of FN and TGF-beta1 in AGE treated GMCs, whereas depletion of USP22 promotes sirtuin-1 degradation and the expression of FN and TGF-beta1 in this cell model.

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And overexpression USP22 in A549 induced an increase of TGF-beta1 expression.

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Moreover, USP22 may up-regulate TGF-beta1 expression.

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Ubiquitin specific protease 22 (USP22) reduced Sirt1 ubiquitination and degradation and decreased FN and TGF-beta1 expression in GMCs under both basal and AGEs treated conditions.

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Modified USP22 increases the amount of TGFB1. 2 / 2

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Furthermore, we have found overexpression of USP22 correlated with high TGF-beta1 expression in the lung ADC tissues.To determine whether USP22 expression in lung ADC cells induced EMT by changing the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP22 decreases the amount of TGFB1.

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USP22 decreases the amount of TGFB1. 2 / 2

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Ubiquitin specific protease 22 (USP22) reduced Sirt1 ubiquitination and degradation and decreased FN and TGF-beta1 expression in GMCs under both basal and AGEs treated conditions.

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Modified USP22 decreases the amount of TGFB1. 1 / 1

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USP22 activates TGFB1.

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USP22 activates TGFB1. 1 / 2

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AP4 transcription is increased by TGF-β1 [ xref ], which, in turn, can be activated by USP22.

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USP22 affects Neoplasms

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USP22 activates Neoplasms.

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USP22 activates Neoplasms. 8 / 10

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To date , no small molecule inhibitors of USP22 have been reported , but given mounting evidence in multiple contexts that USP22 promotes tumor progression , the development of such inhibitors would be desirable .

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In sum , these studies identify USP22 as a regulator of the response to DNA damage , and ultimately define a major node by which USP22 promotes cancer phenotypes .

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A more recently published report indicates that USP22 may promote tumor progression and induce EMT in colorectal carcinoma patients [ 13 ] .

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Despite these advances , the overall mechanisms by which USP22 contributes to cancer progression remain incompletely defined .

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Knockdown of USP22 in an in vivo model was shown to decrease tumor angiogenesis, impair non-homologous DNA damage repair pathways and significantly improve the therapeutic efficacy of cisplatin.

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Apart from activating oncogenes such as BMI-1 and c-MYC , USP22 can inhibit the expression of tumor suppressors such as TP53 through ubiquitination , thus promoting proliferation of tumors [ 87 ] .

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Moreover, the depletion of USP22 was shown to decrease in vivo tumor growth .

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Previous studies have also shown that USP22 can promote tumor progression and induce EMT in various tumors [ 13 , 23 ] .

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USP22 inhibits Neoplasms.

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USP22 inhibits Neoplasms. 1 / 1

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Apart from activating oncogenes such as BMI-1 and c-MYC , USP22 can inhibit the expression of tumor suppressors such as TP53 through ubiquitination , thus promoting proliferation of tumors [ 87 ] .

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USP22 affects CCNB1

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USP22 activates CCNB1. 7 / 9

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Phosphorylation of USP22 at T147 and S237 by CDK1 increases the deubiquitination status of cyclin B1 in a cell cycle dependent manner.

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Moreover, the proteasome inhibitor MG132 protected CCNB1 from degradation in usp22 knockdown cells (XREF_FIG), implying that USP22 mediates CCNB1 stabilization through regulating the proteasomal pathway.

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USP22 mediated CCNB1 stabilization is regulated by both CDK1 and the APC/C E3 ubiquitin ligase complex.

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Given that degradation of CCNB1 is required for cells to exit M phase and enter anaphase [XREF_BIBR, XREF_BIBR], we proposed that USP22 degradation, which presumably allows CCNB1 degradation during late M phase, is necessary for cell cycle regulation.

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Our discovery here, that both USP22 and CCNB1 proteins are elevated and positively associated in human colon cancers, indicates that USP22 mediated CCNB1 stabilization is one possible molecular mechanism underlying its proto-oncogenicity.

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Therefore, APC and CDC20 E3 ligase complex promotes USP22 protein degradation, presumably allowing CCNB1 degradation for cells to exit M phase.

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In addition, Usp22 promotes CRC by stabilizing cyclin B1.

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USP22 bound to Cyclin activates CCNB1. 1 / 1

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USP22 binding to Cyclin B1, promotes cyclin B1 accumulation in the nucleus and inhibits its degradation [XREF_BIBR].

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USP22 bound to CCNB1 activates CCNB1. 1 / 1

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USP22 binding to Cyclin B1, promotes cyclin B1 accumulation in the nucleus and inhibits its degradation [XREF_BIBR].

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USP22 affects PTGS2

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USP22 activates PTGS2.

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USP22 activates PTGS2. 3 / 4

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Ectopic expression of USP22 upregulated the levels of COX-2, whereas expression of the catalytically inactive C185A USP22 mutant had no effect, confirming that USP22 regulates the stability of COX-2 i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP22 inhibits PTGS2.

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USP22 inhibits PTGS2. 1 / 1

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Western blot analysis showed that USP22 siRNA significantly reduced the half-life of COX-2 in A549 cells from 2.5 +/- 0.57 h to 1.18 +/- 0.34 h.

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USP22 affects EGFR

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USP22 activates EGFR.

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USP22 activates EGFR. 5 / 5

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Thus, stabilization and activation of EGFR by USP22 are likely to be important factors in the mechanism underlying the oncogenicity and drug-resistance in EGFR-mutant lung ADCs.

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Of note, more EGFR colocalized with Rab11 in the PC9 cells with overexpression of USP22 than the control cells, which confirms that USP22 enhances EGFR recycling.

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However, our finding on prevention of endocytosis mediated EGFR degradation by USP22 reveals one vital aspect of USP22 's diverse functions.

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Our study suggests that USP22 antagonizes EGFR degradation and amplifies EGFR signaling activity to promote EGFR-TKIs resistance in EGFR mutated lung ADCs.

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We show here that overexpression of USP22 prevents EGFR down-regulation, while shRNA mediated silencing of USP22 enhances EGFR degradation.

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USP22 decreases the amount of SOX2.

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USP22 decreases the amount of SOX2. 8 / 8

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DUBs that have been reported to control developmental processes through deubiquitylating H2B include USP44, which represses genes involved in lineage commitment during mESC maintenance [XREF_BIBR], and USP22, which specifically inhibits expression of the pluripotency factor SOX2 during hESC differentiation [XREF_BIBR].

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In mouse ES cells, Usp22 represses the transcription of the pluripotency factor Sox2, thereby promoting differentiation [XREF_BIBR].

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USP22 is known to bind to the promoter region of Sox2 and negatively regulates Sox2 transcription in embryonic stem cells (ESCs) 47.

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Loss of Usp22 occupancy at the Sox2 locus is associated with elevated levels of H2Bub and increased transcription of Sox2.

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In addition, USP22 occupies the Sox2 promoter and hydrolyzes mono-ubiquitin from ubiquitinated H2B (uH2B), and blocks transcription of the Sox2 locus.

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USP22 has been found to be located directly on the Sox2 promoter and catalyzes deubiquitination of H2B and attenuates Sox2 transcription.

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USP22 is located directly on the Sox2 promoter and negatively regulates Sox2 transcription in ESCs [XREF_BIBR].

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In the recent study by Sussman et al., USP22 was shown to repress the expression of the Sox2 locus that encodes one of the core transcriptional regulators of ES-cell pluripotency (Sussman et al., 2013[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP22 inhibits SOX2.

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USP22 inhibits SOX2. 1 / 2

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Moreover they found USP22 represses the SOX2 promoter in order to control the embryonic stem cell transition from self-renewal to differentiation [XREF_BIBR] Therefore, not only is SOX2 an essential stem cell marker but its suppression is mandatory for cellular differentiation.

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USP22 affects diphenylmethane-4,4'-diisocyanate

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USP22 activates diphenylmethane-4,4'-diisocyanate.

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USP22 activates diphenylmethane-4,4'-diisocyanate. 8 / 8

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Owing to its relationship with the chemotherapeutic resistance of several types of human cancers (Glinsky, 2005), cyclin B1 may also mediate the USP22 induced MDR in HCC cells, which is valuable for future exploration.

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These results confirmed the role of SIRT1 in USP22 induced MDR in HCC cells.

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] Our previous work revealed that USP22 was able to promote HCC stemness by a HIF1alpha / USP22 positive feedback loop and mediate multidrug resistance ( MDR ) by activating the SIRT1 / AKT / MRP1 pathway .

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Taken together, the present study found that USP22 can promote the MDR in HCC cells via activating the SIRT1/AKT/MRP1 pathway.

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XREF_BIBR Ubiquitin specific protease 22 (USP22) mediates the MDR of HCC via the SIRT1/AKT/MRP1 signaling pathway.

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First, we defined SIRT1 as a significant mediator in USP22 driven MDR in HCC.

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Interestingly, we found that modulation of USP22 or SIRT1 could influence the intracellular ADR concentration, which might partly bridge the induction of MDR by USP22 and SIRT1 in HCC cells.

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Together, these results indicate that USP22 could promote the MDR in HCC cells by activating the SIRT1/AKT/MRP1 pathway.

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USP22 increases the amount of diphenylmethane-4,4'-diisocyanate.

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USP22 increases the amount of diphenylmethane-4,4'-diisocyanate. 2 / 2

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Moreover, USP22 knockdown also decreases MDR related genes expression by inhibiting Akt phosphorylation, and USP22 knockdown mediated Smad4 up-regulation is crucial for Akt suppression.

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USP22 knockdown decreased MDR related genes expression through up-regulation of Smad4 and suppression of Akt.

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MYC affects USP22

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MYC activates USP22.

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MYC activates USP22. 4 / 5

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At the posttranscriptional level, c-MYC has been shown to increase USP22 protein but not mRNA levels.

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Furthermore, USP22 acts as an enzymatic component of the SAGA transcriptional cofactor complex and is activated by Myc as an oncogene [38].

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For example, as part of the SAGA complex USP22 promotes transcriptional activation by the Myc oncogene (Zhang et al., 2008b).

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This SIRT1 overexpression is related to enhanced expression of the USP22 deubiquitinase induced by c-MYC, leading to reduced SIRT1 ubiquitination and enhanced stability.

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MYC increases the amount of USP22.

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MYC increases the amount of USP22. 3 / 3

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These results suggest that USP22 positively regulates MYC dependent transcription, which may at least partially explain its oncogenic properties.

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This is significant, as AR upregulation drives the CRPC phenotype, MYC is a known PCa oncogene, and USP22 regulates MYC transcription.

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Taken together, these results indicate that USP22 increases cell migration and invasion by inducing EMT by binding to the promoter of AP4 to activate its transcription.

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These results suggest that while USP22 promotes cell migration and invasion, loss of USP22 sensitizes EGFR mutant NSCLC cells to erlotinib in vitro.

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These results indicate that USP22 increases CRC cell migration and invasion abilities by promoting EMT.

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Indeed, compared with control, we found that the USP22 knockdown cells grew significantly more slowly in H1650 (p < 0.05, Fig. 2 B) and the USP22 overexpression in A549 accelerated cell growth (p < 0.[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The results showed cancer cell migration was significantly inhibited by knockdown of USP22 in H1650 (p < 0.05, Fig. 2 C).

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Therefore, USP22 silencing impairs ATC cell migration and invasion by ablating EMT.

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Our results also demonstrated that USP22 can increase cell migration and invasion abilities via EMT induction.

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Meanwhile, overexpression of USP22 in A549 markedly promoted the cell migration when compared with untreated A549 controls (p < 0.05, Fig. 2 C).

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USP22 increases CRC cell migration and invasion by inducing EMT.

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USP22 affects USP22

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USP22 decreases the amount of USP22.

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USP22 decreases the amount of USP22. 3 / 4

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XREF_FIG, USP22 specific siRNA effectively inhibited USP22 gene transcription and protein expression.

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USP22 siRNA transfection (58 nM) for 24 h was observed to significantly reduce expression of USP22 mRNA and protein in U87 and U251 cells (XREF_FIG).

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The results of western blot analysis showed that USP22R restored the levels of USP22 and COX-2 downregulated by USP22 siRNA.

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USP22 inhibits USP22.

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USP22 inhibits USP22. 2 / 2

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USP22 inhibits Ubiquitin. 6 / 6

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In liver cancer, upregulation of lncRNA HULC activates autophagy by increasing the expression of ubiquitin specific peptidase 22 (USP22) which in turn prevents the ubiquitin mediated degradation of silent information regulator 1 (SIRT1) by removing the conjugated polyubiquitin chains from SIRT1.

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Increasing evidence links deregulation of the ubiquitin specific proteases 22 (USP22) deubitiquitylase to cancer development and progression in a select group of tumor types, but its specificity and underlying mechanisms of action are not well defined.

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On the contrary, the deubiqutinase USP22 antagonizes the ubiquitin ligase complex RNF20/40 on H2B monoubiquitination.

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It belongs to the DUB subset of Machado–Joseph disease (MJD) proteic domain-containing peptidases with Atxn3 (a.k.a. MJD1 and SCA3), encoded by the gene mutated in MJD, also termed type-3 spinocerebellar ataxia (SCA3), and Josephin domain-containing DUbs JosD1 and JosD2 (Table 1.7).27Aggregates formed by polyglutamine-expanded ataxin-7 sequester ubiquitin-specific peptidase USP22 that cannot then fulfill its deubiquitinating function in the SAGA complex, causing cytotoxicity and neurodegeneration [109].

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HULC is overexpressed in HCC as it promotes growth in cancer cells through enhancing ubiquitin specific peptidase 22 (USP22) which reduces ubiquitin mediated degradation of COX-2 protein hence stabilizing and upregulating COX-2 protein [XREF_BIBR].

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Moreover, the study of the corresponding mechanism by which HULC upregulated COX-2 showed that HULC enhanced the level of ubiquitin specific peptidase 22 (USP22), which decreased ubiquitin mediated degradation of COX-2 protein by removing the conjugated polyubiquitin chains from COX-2 and finally stabilized COX2 protein.

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USP22 activates Ubiquitin.

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USP22 activates Ubiquitin. 2 / 2

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Interestingly, the human and fly SAGA complexes possess a module that houses ubiquitin hydrolase activity mediated by the USP22 (human) and Nonstop (fly) proteins.

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As suspected from its domain structure, USP22 is able to hydrolyze a ubiquitin linkage from histone H2B in vitro and endogenous USP22 contributes ubiquitin hydrolase activity to the hSAGA complex.

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USP22 affects KDM1A

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USP22 activates KDM1A.

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USP22 activates KDM1A. 4 / 6

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Our findings demonstrate that nuclear GSK3beta and USP22 mediated KDM1A stabilization is essential for glioblastoma tumorigenesis.

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USP22 activates cell differentiation.

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USP22 activates cell differentiation. 4 / 4

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In addition, Sussman RT, et al. have reported that USP22 promotes embryonic stem cell differentiation through transcriptional repression of Sex determining region Y-box 2 (Sox2) XREF_BIBR.

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On the contrary, Usp22 overexpression leads to increased differentiation of ESCs into EBs even in the absence of stimuli that drives differentiation [XREF_BIBR].

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USP22 suppression also diminishes iNKT17 and iNKT1 differentiation but favors iNKT2 polarization without altering conventional T cell activation and differentiation.

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Knockdown of Usp22 shortened the half-life of Hes1, delayed its oscillation, and enhanced neuronal differentiation in mouse developing brain, whereas mis expression of Usp27x reduced neuronal differentiation.

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USP22 inhibits cell differentiation.

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USP22 inhibits cell differentiation. 3 / 3

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Another study in mice showed that Usp22 negatively regulates neuronal differentiation in the mouse developing brain.

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On the contrary, depletion of USP22 delays Hes1 oscillation and thereby, induces neuronal differentiation from neuronal progenitor stem cells .

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For instance, two histone directed DUBs, USP44 and USP22, are antagonistically regulated in their mRNA expression to ensure faithful stem cell differentiation [XREF_BIBR - XREF_BIBR].

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USP22 affects autophagy

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USP22 activates autophagy.

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USP22 activates autophagy. 5 / 6

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Beyond regulating apoptosis, the USP22 and SIRT1 pathway may also modulate autophagy.

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USP22 induced autophagy was also found to enhance cell proliferation and resistance to starvation and chemotherapeutic drugs in Panc-1 cells, therefore expressing an overall effect that promotes cell survival.

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In addition, in a pancreatic cancer cell line (Panc-1), USP22 overexpression stimulates autophagy through the ERK1/2 pathway and hereby promotes resistance to gemcitabine treatment [XREF_BIBR].

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Taken together, these findings reveal a potential mechanism underlying the chemoresistance of PC cells mediated by the regulation of USP22 mediated autophagy by miR-29c, suggesting potential targets and therapeutic strategies in PC.

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USP22 upregulation may thus inhibit apoptosis and stimulate autophagy in response to treatment with DNA damaging agents or targeted inhibitors to promote resistance to chemotherapy in cancer patients.

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USP22 inhibits autophagy.

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USP22 inhibits autophagy. 1 / 1

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MicroRNA-29c Increases the Chemosensitivity of Pancreatic Cancer Cells by Inhibiting USP22 Mediated Autophagy.

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USP22 affects Chromosomal Instability

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USP22 inhibits Chromosomal Instability.

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USP22 inhibits Chromosomal Instability. 6 / 6

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Having established that reduced USP22 expression induces CIN in short-term (< 1 week) siRNA based experiments, we now sought to determine the impact long-term USP22 depletion has on CIN.

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USP22 Silencing Induces CIN Associated Phenotypes.

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Furthermore, two-sample Kolmogorov-Smirnov (KS) tests revealed statistically significant increases (siUSP22-2, siUSP22-3) and a decrease (siUSP22-Pool) in cumulative nuclear area frequency distributions relative to siControl (XREF_FIG D; Table S5) that are consistent with reduced USP22 expression inducing CIN.

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In agreement with this possibility, we show that diminished USP22 expression induces CIN, highlighting a novel role for USP22 as a tumor suppressor that is essential to maintain mitotic fidelity and chromosome stability.

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In this regard, while USP22 has been proposed as a novel therapeutic target based on its oncogenic functions [XREF_BIBR, XREF_BIBR, XREF_BIBR], our work suggests that USP22 inhibition will induce CIN that may promote cancer progression and/or the development of secondary malignancies.

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Further, we identify USP22 as a novel CIN gene, indicating that USP22 deletions in tumors may drive CIN and contribute to oncogenesis.

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USP22 activates Chromosomal Instability.

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USP22 activates Chromosomal Instability. 1 / 1

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In addition, we reveal that USP22 deficiency impairs H2Bub1 removal in early mitosis and induces CIN.

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USP22 affects adenosine 5'-(pentahydrogen tetraphosphate)

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USP22 increases the amount of adenosine 5'-(pentahydrogen tetraphosphate).

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USP22 increases the amount of adenosine 5'-(pentahydrogen tetraphosphate). 6 / 6

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As shown in Figure XREF_FIG, USP22 activates AP4 expression during EMT induction.

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Moreover, USP22 up-regulation induces EMT by directly increasing AP4 transcription, resulting in CRC cell metastasis to the lungs in vivo.

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In summary, USP22 induces EMT by activating AP4 transcription to enhance CRC cell migration and invasion.

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USP22 induces EMT by activating AP4 transcription.

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USP22 up-regulation enhances CRC cell migration and invasion and EMT related marker and AP4 expression, but these effects are partly blocked by AP4 knockdown.

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The key findings of the study are as follows : (i) USP22 enhances CRC cell migration and invasion by inducing EMT, (ii) USP22 directly increases AP4 transcription to induce EMT and promote CRC cell metastasis to the lungs in vivo, and (iii) USP22 and AP4 overexpression is related to CRC progression and liver metastasis and poor outcomes in CRC patients.

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USP22 activates adenosine 5'-(pentahydrogen tetraphosphate).

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USP22 activates adenosine 5'-(pentahydrogen tetraphosphate). 1 / 1

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These results lend further support to the results of our vitro experimental studies, as they showed that USP22 promotes CRC cell metastasis by activating AP4 to induce EMT.

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USP22 affects CDH1

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USP22 increases the amount of CDH1.

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USP22 increases the amount of CDH1. 3 / 3

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USP22 downregulation significantly increased the expression of E-cadherin (epithelial marker) but decreased the expression of N-cadherin and vimentin (mesenchymal markers) (XREF_FIG).

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In this study, we showed that USP22 depletion significantly decreased the expressions of BMI-1, vimentin, and snail and increased E-cadherin expression in ATC cells.

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USP22 inhibits CDH1.

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USP22 inhibits CDH1. 2 / 2

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Immunoblot analysis confirmed that USP22 knockout upregulated E-cadherin, p16; reduced ALDH1A3, Cyclin E1, c-Myc, and attenuated activation of AKT and ERK pathways in these cells.

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USP22 downregulation significantly increased the expression of E-cadherin ( epithelial marker ) but decreased the expression of N-cadherin and vimentin ( mesenchymal markers ) ( Fig. 4 ) .

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USP22 decreases the amount of CDH1.

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USP22 decreases the amount of CDH1. 1 / 1

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In this study, we showed that USP22 depletion significantly decreased the expressions of BMI-1, vimentin, and snail and increased E-cadherin expression in ATC cells.

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Modified USP22 decreases the amount of CDH1. 1 / 1

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SP1 affects USP22

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SP1 decreases the amount of USP22.

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SP1 decreases the amount of USP22. 1 / 3

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For example, SP1 and protein kinase A/cAMP response element binding protein could bind to the USP22 promoter to suppress or promote USP22 transcription, respectively.

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USP22 increases the amount of TERF1.

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Modified USP22 increases the amount of TERF1. 2 / 2

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Conversely, overexpression of wild-type (but not catalytically inactive) USP22 leads to increased TRF1 levels.

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Furthermore, expression of wt-USP22, but not the C185S mutant, was able to partially restore TRF1 levels in cells depleted for endogenous USP22 (XREF_FIG, compare panels 4, 5 and 6).

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USP22 activates Cyclin.

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USP22 activates Cyclin. 3 / 3

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Hence, USP22 overexpression was associated with reduced p21 and p27 levels and increased abundance of Cyclin D1, CDK4 and CDK6, which collectively form a complex that promotes G1 progression [XREF_BIBR].

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In addition, Usp22 promotes CRC by stabilizing cyclin B1.

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USP22 bound to CCNB1 activates Cyclin. 1 / 1

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USP22 binding to Cyclin B1, promotes cyclin B1 accumulation in the nucleus and inhibits its degradation [XREF_BIBR].

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USP22 bound to Cyclin activates Cyclin. 1 / 1

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USP22 binding to Cyclin B1, promotes cyclin B1 accumulation in the nucleus and inhibits its degradation [XREF_BIBR].

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USP22 inhibits Cyclin.

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USP22 inhibits Cyclin. 1 / 1

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USP22 decreases the amount of Cyclin.

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USP22 decreases the amount of Cyclin. 1 / 1

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Mechanistically, we found that USP22 depletion dramatically decreased Akt phosphorylation and cyclin D2 expression.

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E3_Ub_ligase affects USP22

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E3_Ub_ligase inhibits USP22. 6 / 6

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Therefore, APC and CDC20 E3 ligase complex promotes USP22 protein degradation, presumably allowing CCNB1 degradation for cells to exit M phase.

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Moreover , anaphase-promoting complex cell division cycle protein 20 ( APCCDC20 ) , an E3 ubiquitin ligase , promotes USP22 degradation in a cell cycle-dependent manner ( 61 ) .

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USP22 is degraded by the APC/C E3 ubiquitin ligase complex, which also targets CCNB1 for destruction [XREF_BIBR, XREF_BIBR], thereby allowing cells to exit from mitosis, presumably by facilitating CCNB1 degradation.

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In contrast, the APC and CDC20 E3 ligase complex negatively regulates USP22 activity by targeting it for degradation, presumably allowing CCNB1 downregulation so that cells can exit mitosis and enter anaphase.

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To identify the E3 ligase that degrades USP22, we tested the interaction between USP22 and FBW7, CDC20, and CDH1, all of which are active during exit from mitosis [XREF_BIBR, XREF_BIBR].

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Our study demonstrates that USP22 is also a substrate of the APC/C E3 ligase complex, which degrades USP22 during cell exit from M phase.

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USP22 affects transcription, DNA-templated

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USP22 activates transcription, DNA-templated.

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USP22 activates transcription, DNA-templated. 5 / 5

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Transcriptionally, USP22 leads to H2BK120Ub on chromatins among the FOXP3 locus to enhance its transcription.

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USP22 positively regulated transcription factor FOXP3 activity in mouse regulatory T (T reg) cells.

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At the biochemical level, these Polycomb proteins function as global transcriptional repressors by catalyzing the ubiquitylation of histone H2A. In yeast, the USP22 homolog functions as a transcriptional coactivator by removing ubiquitin from a distinct core histones, H2B. Given that USP22 is expressed in cancer as part of an 11 gene signature that includes transcriptional repressors which ubiquitylate H2A, it seemed possible that USP22 might activate transcription in part via the deubiquitylation of this same substrate.

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Subsequently, it was demonstrated that USP22 knockdown inhibited the growth of an RCC cell line ACHN and downregulated the protein level of survivin, accompanied by an increased level of cleaved-caspase-3.

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Modified USP22 increases the amount of BIRC5. 1 / 1

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By contrast, overexpression of USP22 promoted the growth of ACHN cells, upregulated the expression of survivin and decreased the level of cleaved-caspase-3.

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USP22 inhibits BIRC5.

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100 Another DUB, USP22, also stabilizes PD-L1 in tumor cells via deubiquitination and suppresses antitumor immunity in mouse tumor models.

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These findings are consistent with the idea that USP22 promotes the non T cell inflamed TME and suppresses antitumor immunity in PDA.

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Collectively, these experiments suggest that USP22 expression in PDA tumors cells suppresses antitumor immunity and confers resistance to immunotherapy.

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Tumor cell-intrinsic USP22 suppresses antitumor immunity in pancreatic cancer.

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What more excited is that USP22 can inhibit the antitumor immunity, efficacy of PDL1 targeted immunotherapy by inhibiting the deubiquitinase of PDL1 (CD274) [XREF_BIBR], which is consistent with our results.

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USP22 affects Stomach Neoplasms

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USP22 activates Stomach Neoplasms.

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USP22 activates Stomach Neoplasms. 4 / 4

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USP22 knockdown significantly decreased in vitro survival, proliferation, migration, and invasiveness of GC cells compared with the controls.

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USP22 silencing inhibits GC cells proliferation.

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Meanwhile, the colony formation assays of MGC-803 cells also revealed that USP22 knockdown suppressed the proliferative ability of GC cells.

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USP22 inhibits Stomach Neoplasms.

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USP22 inhibits Stomach Neoplasms. 1 / 1

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Knockdown of USP22 suppresses GC xenografts growth.

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USP22 affects FOXM1

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USP22 increases the amount of FOXM1.

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USP22 increases the amount of FOXM1. 3 / 4

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Mechanistically, it has been reported that USP22 induces β-catenin nuclear localisation and upregulates FoxM1 expression to promote G1/S cell cycle transition and cell proliferation (Ning et al., 2014).

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USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via promoting beta-catenin nuclear localization.

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USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via beta-catenin nuclear localization and is associated with poor prognosis in stage II pancreatic ductal adenocarcinoma.

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USP22 activates FOXM1.

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As the Ubp8 ortholog USP22 was recently shown to interact with, deubiquitinate, and stabilize the Sir2 ortholog Sirt1, and conversely Sirt1 has been shown to mediate deacetylation of USP22 and the SAGA coactivator complex, the discovery of genetic and functional relationships between Sgf73, Ubp8, and Sir2 in yeast strongly suggests that mutant ataxin-7 protein could be impairing the function of not only Gcn5 in the context of the STAGA complex, but also USP22 in the deubiquitinase module.

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USP22 affects PI3K

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USP22 activates PI3K.

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USP22 activates PI3K. 3 / 3

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Previous study also showed that USP22 promotes cell cycle progression by positively regulating the PI3K and Akt pathway [XREF_BIBR].

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These results suggest that USP22 downregulation inhibits OS cells by suppressing the PI3K and Akt pathway.

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USP22 increases the amount of BCL2. 2 / 2

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USP22 knockdown also decreased the expression of Bcl-XL and Bcl-2 and increased the expression of cleaved-caspase 3 and cleaved-caspase 9.

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USP22 activates inflammatory response.

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USP22 activates inflammatory response. 3 / 3

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Taken together, the findings of the present study have demonstrated for the first time that USP22 inhibition attenuates high glucose induced podocyte injuries and inflammation.

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Silencing of USP22 suppressed ROS production and inflammation while inhibition of USP14 reduced the accumulation of oxidized proteins.

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We further showed that the overexpression of USP22 increased inflammation, while knocking down BRD4 suppressed the inflammatory response in AML-12 cells.

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USP22 inhibits inflammatory response.

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USP22 inhibits inflammatory response. 1 / 1

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The knockout of Usp22 increased inflammation associated symptoms after DSS treatment locally and systemically.

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USP22 affects cell death

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USP22 activates cell death.

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USP22 activates cell death. 2 / 3

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USP22 activates USP51. 2 / 2

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Equal numbers of cells expressing shRNAs that specifically target USP27X or USP51, but not USP22 (XREF_FIG), or expressing control shRNA, were seeded and monitored for proliferation by cell counts 72 hours later.

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Equal numbers of cells expressing shRNAs that specifically target USP27X or USP51, but not USP22, or expressing control shRNA, were seeded and monitored for proliferation by cell counts 72 hr later.

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USP22 affects USP27X

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USP22 inhibits USP27X.

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USP22 inhibits USP27X. 2 / 2

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To determine whether USP22 blocks association of USP27X and USP51 with SAGA, we isolated GCN5 associated proteins after shRNA mediated depletion of USP22 (XREF_FIG, lanes 2 and 3 and 5 and 6).

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To determine whether USP22 blocks association of USP27X and USP51 with SAGA, we isolated GCN5 associated proteins after shRNA mediated depletion of USP22.

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USP22 activates USP27X.

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USP22 activates USP27X. 2 / 2

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USP22 increases the amount of MDM4. 3 / 3

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In addition, similar to our in vitro findings, USP22 silencing led to a decreased level of MDMX and increased levels of p53 pathway proteins in xenograft tumor tissues (XREF_FIG C).

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Interestingly, we found that in A549 and NCI-H460 cells, USP22 silencing, while activating the p53 pathway, decreased MDMX protein expression (XREF_FIG C), which was confirmed with immunofluorescence (IF) analysis (XREF_FIG D).

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Additionally, USP22 silencing downregulates MDMX protein expression and activates the p53 pathway.

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USP22 activates MDM4.

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USP22 activates MDM4. 1 / 1

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USP22 Silencing Down-Regulates MDMX and Up-Regulates the p53 Pathway in NSCLC Cells.

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USP22 affects FBP1

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USP22 activates FBP1.

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USP22 activates FBP1. 3 / 3

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Moreover, it has been shown that USP22 promotes cell growth by regulating the far upstream element (FUSE)-binding protein 1 (FBP1), a transcriptional regulator of p21 [XREF_BIBR].

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Our results showed that USP22 silencing downregulated COX-2 and FBP1 in A549 and NCI-H460 cells compared to control siRNA.

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USP22 inhibits FBP1.

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USP22 inhibits FBP1. 1 / 1

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Similarly, as a deubiquitinating enzyme, USP22 silenced leads to increased FBP1 ubiquitination and decreased FBP1 protein occupancy at the p21 gene XREF_BIBR.

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USP22 affects DNA Damage

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USP22 activates DNA Damage.

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USP22 activates DNA Damage. 3 / 3

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Knockdown of USP22 in an in vivo model was shown to decrease tumor angiogenesis, impair non-homologous DNA damage repair pathways and significantly improve the therapeutic efficacy of cisplatin.

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According to that model, USP22 enhances DNA damage repair and cisplatin resistance by deubiquitinating histone H2A, which in turn facilitates the phosphorylation of histone H2AX.

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USP22 inhibits DNA Damage.

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Modified USP22 inhibits DNA Damage. 1 / 1

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USP22 affects Cell Survival

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USP22 inhibits Cell Survival.

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USP22 inhibits Cell Survival. 2 / 2

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Similarly, Zhao et al. reported that USP22 depletion suppressed cell survival and proliferation as well as tumor growth and lung metastasis of anaplastic thyroid carcinoma cells XREF_BIBR.

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Cell viability assessed with the MTT assay showed that knock-down of USP22 and COX-2 significantly reduced cell viability to approximately 63% and 47%, respectively, of control cells, whereas overexpr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP22 activates Cell Survival.

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USP22 activates Cell Survival. 2 / 2

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KAT2A inhibits USP22.

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KAT2A inhibits USP22. 1 / 2

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Loss of Gcn5 leads to depletion of Usp22 and the DUB module from SAGA, compromising Usp22 activity, leading to telomere fusions [XREF_BIBR].

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KAT2A activates USP22.

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KAT2A activates USP22. 2 / 2

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Loss of Gcn5 impairs the deubiquitinating activity of Usp22 [XREF_BIBR], which partners with Atxn7 in the DUB module.

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GCN5 has been shown to support the association of USP22 with the SAGA complex.

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AKT affects USP22

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AKT inhibits USP22.

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AKT inhibits USP22. 3 / 3

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Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells.

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These results suggest that USP22 knockdown induced chemosensitivity of HCC cells by down-regualting PI3K and Akt, and Smad4 mediated Akt suppression as well.

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USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt.

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AKT activates USP22.

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AKT activates USP22. 1 / 1

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Western blot analysis was conducted to detect the activation of RAS and ERK and PI3K and AKT signaling in USP22 overexpressing SGC7901 cells and xenograft tumor tissues.

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5-formyluracil affects USP22

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5-formyluracil activates USP22.

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5-formyluracil activates USP22. 3 / 3

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After the mice injected with Bel/Fu cells with siRNA interference of USP22 expression were treated with 5-FU, the size of the subcutaneous xenografts significantly decreased, suggesting that downregulation of USP22 expression mitigated 5-FU resistance and increased the sensitivity of HCC to chemotherapy drugs, which may be related to the physiological function of USP22 to form a complex with BMI1.

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After the Bel/Fu cells were injected into nude mice, the mean diameter of the subcutaneous xenografts that developed was 1.5 cm, whereas for mice injected with Bel/Fu cells with stable expression of USP22 siRNA, the mean diameter was smaller (1.4 cm, n = 6, P < 0.05, XREF_FIG); after the mice injected with Bel/Fu cells were treated with 5-FU, the mean diameter of xenografts was smaller (1.2 cm, n = 6, P < 0.05, XREF_FIG); after the mice injected with Bel/Fu cells with stable expression of USP22 siRNA were treated with 5-FU, the mean diameter of xenografts was 0.9 cm, significantly smaller than that observed in mice injected with Bel/Fu cells alone (n = 6, P < 0.05, XREF_FIG).

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Remarkably, silencing USP22 reduced the tumor volume of BEL/FU cells treated with 5-FU (BEL/FU control shRNA cells treated with 5-FU vs BEL/FU USP22 shRNA treated with 5-FU, 945 +/-545mm 3 vs 372 +/-228mm 3, P < 0.05).

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5-formyluracil inhibits USP22.

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5-formyluracil inhibits USP22. 1 / 1

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USP22 affects FOXP3

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USP22 activates FOXP3.

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USP22 activates FOXP3. 2 / 2

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USP22 positively regulated transcription factor FOXP3 activity in mouse regulatory T (T reg) cells.

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USP22 decreases the amount of CDH2. 2 / 2

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AP4 down-regulation partially reversed the increases in N-cadherin and vimentin expression levels induced by USP22 up-regulation; however, no changes in USP22 expression levels were observed.

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USP22 downregulation significantly increased the expression of E-cadherin (epithelial marker) but decreased the expression of N-cadherin and vimentin (mesenchymal markers) (XREF_FIG).

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Modified USP22 decreases the amount of CDH2. 1 / 1

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USP22 increases the amount of CDH2.

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USP22 increases the amount of CDH2. 1 / 1

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USP22 affects CD274

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USP22 activates CD274.

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USP22 activates CD274. 2 / 2

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Our hypothesis is that the poor clinical efficacy of the treatments targeting PD-L1 may be due to the stabilization of PD-L1 mediated by USP22, abolishing the effect of anti-PD-L1 drugs.

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On the one hand, USP22 could directly regulate PD-L1 stability through deubiquitination.

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USP22 inhibits CD274.

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USP22 inhibits 5-formyluracil. 2 / 2

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USP22 activates BAX.

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USP22 activates BAX. 1 / 1

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MIR101-1 activates USP22. 2 / 2

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Bisphenol A increases the amount of USP22. 1 / 1

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No evidence text available

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Bisphenol A decreases the amount of USP22.

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Bisphenol A decreases the amount of USP22. 1 / 1

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Modified USP22 increases the amount of ZEB1. 1 / 1

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Our studies revealed that the overexpression of USP22 in PANC-1 cells promoted Ezrin redistribution and phosphorylation and cytoskeletal remodeling, upregulated expression of the transcription factors Snail and ZEB1 to promote EMT, and increased cellular invasion and migration.

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USP22 activates ZEB1.

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USP22 activates ZEB1. 1 / 1

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USP22 increases the amount of SHH. 1 / 1

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Ubiquitination assays manifested that LINC01426 and USP22 modulated SHH ubiquitination levels.

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USP22 decreases the amount of SHH.

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USP22 decreases the amount of SHH. 1 / 1

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USP22 inhibits Genomic Instability. 1 / 1

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By impacting H2Bub1 levels, USP22 partakes in multiple pathways required for the maintenance of genome stability, and USP22 expression may be required to prevent aberrant events underlying genome instability.

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USP22 activates Genomic Instability.

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USP22 activates Genomic Instability. 1 / 1

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USP22 inhibits ERBB2. 1 / 1

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Strikingly , we found that USP22 actively suppresses UPR induction in HER2 + - BC cells by stabilizing the major endoplasmic reticulum ( ER ) chaperone HSPA5 .

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USP22 activates ERBB2.

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USP22 activates ERBB2. 1 / 1

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USP22 inhibits BCL2L1. 1 / 1

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In addition, USP22 knockdown combined with 5-Fu treatment further enhanced the down-regulation of Bcl-XL, Bcl-2 and up-regulated cl-caspase 3 and cleaved-caspase 9.

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USP22 increases the amount of BCL2L1.

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USP22 increases the amount of BCL2L1. 1 / 1

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PI3K inhibits USP22. 1 / 1

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These results suggest that USP22 knockdown induced chemosensitivity of HCC cells by down-regualting PI3K and Akt, and Smad4 mediated Akt suppression as well.

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PI3K activates USP22.

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PI3K activates USP22. 1 / 1

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Phosphorylated CREB1 inhibits USP22. 1 / 1

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The addition of THP abrogates PKA activity and decreases CREB-1 phosphorylation,, thereby inhibiting USP22 expression and USP22 mediated tumorigenic activity.

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