USP39 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 39
HGNC Gene Symbol
USP39
Identifiers
hgnc:20071 NCBIGene:10713 uniprot:Q53GS9
Orthologs
mgi:107622 rgd:1308103
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP39
Number of Papers
58 retrieved on 2022-05-22

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) CCLE Significant CMAP Score CMAP Type
LSM5 LSM5 homolog, U6 small nuclear RNA and mRNA degradation associated 0.357 Reactome (4) -0.58 -3.29 1.09e-13
ABCE1 ATP binding cassette subfamily E member 1 0.346 0.02 0.05 7.38e-01
TTK TTK protein kinase 0.344 0.03 0.10 6.39e-01
CCT8 chaperonin containing TCP1 subunit 8 0.337 0.21 1.09 1.64e-04
ANAPC10 anaphase promoting complex subunit 10 0.333 0.14 0.68 1.87e-02
PES1 pescadillo ribosomal biogenesis factor 1 0.329 Reactome (1) 0.59 3.16 5.61e-34
SKP1 S-phase kinase associated protein 1 0.32 -0.14 -0.86 1.81e-02

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP39using 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

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP39 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
RSRC2 arginine and serine rich coiled-coil 2 5.57e-01 3.97e-09 1.97e-05
TTI2 TELO2 interacting protein 2 9.21e-01 2.96e-07 7.34e-04
RACK1 receptor for activated C kinase 1 -2.63e-01 2.13e-06 3.53e-03
MTND2P28 MT-ND2 pseudogene 28 5.59e-01 1.26e-05 1.56e-02
BMP4 bone morphogenetic protein 4 5.78e-01 3.22e-05 3.06e-02
MTPN myotrophin 3.60e-01 3.70e-05 3.06e-02
FEZ2 fasciculation and elongation protein zeta 2 -6.17e-01 6.70e-05 4.31e-02
PTP4A2 protein tyrosine phosphatase 4A2 -3.70e-01 6.97e-05 4.31e-02
HLTF helicase like transcription factor 5.94e-01 9.50e-05 4.71e-02
MT-CO2 mitochondrially encoded cytochrome c oxidase II -2.41e-01 8.70e-05 4.71e-02

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 USP39 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
USP39 deubiquitinates AURKB. 1 / 1
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USP39 deubiquitinates aurora B kinase maintaining spindle assembly checkpoint integrity [103] while USP44 stabilizes Mad2/Cdc20 complex inhibiting premature activation of the APC/CCdh1?complex
USP39 deubiquitinates CHEK2. 1 / 1
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Mechanistically, USP39 deubiquitinates and stabilizes CHK2, which in turn enhances CHK2 stability.
USP39 deubiquitinates USP4. 1 / 1
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USP39 binds with USP4 via its UBL domain and correspondingly enhances the stability of USP4 in T cells [XREF_BIBR, XREF_BIBR], implying that USP39 might be deubiquitylating USP4.
USP39 leads to the deubiquitination of SP1. 1 / 1
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USP39 promotes tumorigenesis by stabilizing and deubiquitinating SP1 protein in hepatocellular carcinoma.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

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Furthermore, USP39 knockdown in VSMCs significantly reduced proliferation compared with cells transfected with control siRNA (P = 0.0238; XREF_FIG).

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Reduced USP39 expression inhibits malignant proliferation of medullary thyroid carcinoma in vitro.

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Knockdown of USP39 could inhibit the proliferation and induce apoptosis of SMMC-7721 cells, as well as the growth of xenograft tumors in nude mice.
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USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1.

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A sumosylated USP39 has been shown to promote the proliferation of PC-3 and LNcap cells [XREF_BIBR].

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USP39 knockdown inhibited the proliferation and colony formation of A549 and HCC827 cells and decreased tumorigenic potential in nude mice.

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USP39 silencing via lentivirus mediated short hairpin RNA (shRNA) significantly suppressed melanoma cell proliferation, induced G0/G1 cell cycle phase arrest, and increased apoptosis in vitro.

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The inducible shRNA mediated downregulation of USP39 expression markedly reduced the proliferation and colony forming ability of MDA-MB-231 cells, while overexpression of USP39 by the inducible system did not promote cancer cell proliferation.

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Moreover, recent studies indicated that knocking down USP39 promoted cell proliferation in different types of cancers [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR].

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In addition, overexpression of HMGA2 rescued the inhibition of proliferation, invasion and xenograft growth induced by silencing USP39.

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Moreover, USP39 depletion inhibits HCC cell proliferation and metastasis by promoting ZEB1 degradation.

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USP39 overexpression deprived miR-133a inhibitor mediated suppression of cell proliferation, suggesting that USP39 is involved in miR-133a-mediated biological role in gastric cancer cell HGC-27 (P < 0.0001) (XREF_FIG).

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Furthermore, knockdown of USP39 inhibited VSMC cell proliferation and the expression of cyclin D1 and cyclin-dependent kinase 4, as analyzed via cell counting, MTT assay and western blotting.

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In addition, it has been reported that overexpression of MGC-803 cells and knockdown of USP39 may inhibit MGC-803 cell proliferation and induce cell cycle arrest.

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Knockdown of USP39 suppressed the proliferation and cell cycle progression, and induced apoptosis, accompanied by the reduction of EGFR in both mRNA and protein levels in PC-3 and DU145 cells.

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Knockdown of USP39 significantly inhibited proliferation of TT cells in vitro.

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Knockdown of USP39 significantly decreased cell proliferation and caused cell cycle arrest at G2/M phase.

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We further observed that USP39 downregulation inhibits the cell proliferation and migration of A549 and HCC827 cells.

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Knockdown of USP39 remarkably inhibited the cell proliferation of osteosarcoma cells.

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Down-regulation of USP39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells [XREF_BIBR].
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Meanwhile, knockdown of USP39 could arrest cell cycle at G2/M via cyclin dependent pathway and promoted apoptosis through PARP cleavage [XREF_BIBR - XREF_BIBR].

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Collectively, our data suggest that knocking down USP39 induces cell cycle arrest at S phase and G2/M phase, and results in apoptosis, and that the mechanism of apoptosis induced by USP39 knockdown may be related to DNA damage.

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Silencing USP39 can inhibit the proliferation of melanoma cells in vitro and in vivo, induce G0/G1 arrest, and promote apoptosis.

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Conversely, overexpression of USP39 attenuates apoptosis in RKO cells.

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In order to further demonstrate the mechanisms of apoptosis induced by USP39 knockdown, the levels of cleaved cas3 and cleaved cas9 were increased in response to USP39 knockdown (XREF_FIG E, F).

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These results suggested USP39 knockdown could promote U2OS cell apoptosis.

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Furthermore, we demonstrate that USP39 depletion promotes apoptosis induced by cisplatin, which is related with the induction of oxidative stress and DNA damage response.

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Mechanism study showed that USP39 knockdown induced the arrest of cell cycle and apoptosis of leukemia cells.

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These results suggested that knockdown of USP39 in SMMC-7721 cells could induce cell apoptosis via altering the expression of Bax, Caspase 9, Caspase 3 and PARP.

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In addition, the inhibition of USP39 induced G0/G1-phase arrest and apoptosis of the cells.
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Knockdown of USP39 induces cell cycle arrest and apoptosis in melanoma.

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Down-regulation of USP39 induced SMMC-7721 cells apoptosis.

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Knockdown of USP39 suppressed the proliferation and cell cycle progression, and induced apoptosis, accompanied by the reduction of EGFR in both mRNA and protein levels in PC-3 and DU145 cells.

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The group of silencing USP39 increased the apoptotic cells (early apoptosis and late apoptosis) by 13-fold, as compared to the group of shCon (Additional file 1 : Figure S1A and B).

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Second, we found that knocking down USP39 induces apoptosis of A549 and HCC827 cells, upregulates cleaved cas3, cleaved cas9 and DNA damage makers (53BP1 and gammaH2AX) [XREF_BIBR].

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Depletion of USP39 promotes apoptosis of U2OS cells.

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Down-regulation of USP39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells [XREF_BIBR].

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Knocking-down of USP39 promotes the cell apoptosis and arrest of the cell cycle, whereas SP1 forcefully reversed these effects.
USP39 affects cell cycle
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USP39 inhibits cell cycle.
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In addition, flow cytometry analysis in the present study identified that the knockdown of USP39 induced cell cycle arrest in the G 2 / M phases, which may have induced the inhibition of proliferation.

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In melanoma, knockdown USP39 inhibited cell growth and induced cell cycle arrest and apoptosis.

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A further analysis indicated suppression of USP39 arrested cell cycle progression at G2/M phase via p21 dependent way.

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Our loss-of-function experiments demonstrated that knockdown of the expression of USP39 repressed the proliferation of leukemia cells, induced cell cycle arrest, and cell apoptosis.

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However, treated with PFT-alpha reduced the up-regulation of p21 and BAX induced by USP39 knockdown, but had no effect on the down-regulation of cell cycle related proteins (CDK1 and CyclinB1 and CDK2 and CyclinA2) induced by USP39 knockdown.

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These results indicate that knockdown of USP39 induced G2/M phase cell cycle arrest via suppression of the CDK1 and Cyclin B1 complex.

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Similarly, we observed that USP39 knockdown induced cell cycle arrest at G2/M phase in Jurkat cells (XREF_FIG C, D).

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Flow cytometric analysis showed that USP39 knockdown induced cell cycle arrest at G2/M phase and enhanced cell apoptosis in 95D cells.

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To evaluate the role of cell cycle-regulatory molecules in knockdown of USP39 induced G2/M cell cycle arrest, we examined the effect of USP39 knockdown on cell cycle-regulatory molecules, including p21, CDK1 and cyclin A2.

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We showed that USP39 knockdown induced the cell cycle arrest at G2/M phase in two lines of leukemia cells.
USP39 activates cell cycle.
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Knockdown of USP39 induces cell cycle arrest and apoptosis in melanoma.

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First, we observed that depletion of USP39 contributes to abnormal cell cycle distribution by inducing cell cycle arrest at G2/M.

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Furthermore, suppression of USP39 arrested cell cycle progression at G 2 / M phase in SMMC-7721cells.

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Meanwhile, knockdown of USP39 could arrest cell cycle at G2/M via cyclin dependent pathway and promoted apoptosis through PARP cleavage [XREF_BIBR - XREF_BIBR].

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Knockdown of endogenous USP39 expression could suppress the oncogenic properties of osteosarcoma cells and induce cell cycle arrest at G2/M phase, promote apoptosis through PARP cleavage.

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Knockdown of USP39 induced cell cycle arrest and its effect on cell cycle-regulatory molecules.

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This observation indicated that the cell cycle was blocked at the G2/M phase by USP39 knockdown in HL-60 cells (XREF_FIG A, B).

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Taken together, our findings implicate that USP39 promotes the development of human leukemia by regulating cell cycle, survival, and proliferation of the cells.

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Knockdown of USP39 significantly decreased cell proliferation and caused cell cycle arrest at G2/M phase.

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USP39 knockdown inhibits cell cycle progression.
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USP39 promotes proliferation and invasion in vitro and tumor growth in vivo.

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USP39 promoted the invasion of glioma cells in vivo and reduced the overall survival of the mice.

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Knockdown of USP39 in U251 and U87 cell lines significantly inhibited their migration and invasion in vitro .

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USP39 increases proliferation and invasion of ovarian cancer cells and promotes growth of xenograft tumors in mice.

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Subsequent functional experiments revealed that USP39 promoted the proliferation and invasion of ovarian cancer cells in vitro and tumor growth in vivo.

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In addition, overexpression of HMGA2 rescued the inhibition of proliferation, invasion and xenograft growth induced by silencing USP39.

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Moreover, USP39 knockdown significantly inhibited migration and invasion of A549 and HCC827 cells, also via activation of the p53 pathway, and downregulation of MMP2 and MMP9.

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USP39 promotes proliferation / invasion in vitro and tumor growth in vivo .

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Third , we demonstrated that USP39 knockdown inhibits cell migration and invasion by upregulating p53 and the downstream proteins MMP2 and MMP9 [ 31 ] .

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Third, we demonstrated that USP39 knockdown inhibits cell migration and invasion by upregulating p53 and the downstream proteins MMP2 and MMP9 [XREF_BIBR].

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Knockdown of USP39 in U251 and U87 cell lines significantly inhibited their migration and invasion in vitro.
USP39 affects EGFR
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USP39 activates EGFR.
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USP39 activates EGFR. 3 / 5
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The results demonstrated that the level of the 3 '-end of EGFR decreased (P = 0.0015) more sharply than that of the 5 '-end (P = 0.0069), and the ratio ofthe 3 '-end to 5 '-end levels was significant decreased (P = 0.0297), implying that knockdown of USP39 might inhibit the transcription elongation of EGFR, and might produce unstable EGFR mRNA fragments lacking the 3 '-UTR.

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To verify whether the regulatory effect of USP39 was EGFR specific, ectopic expression of USP39 were performed in PC-3 and DU145 cells, which showed that overexpressed USP39 upregulated EGFR mRNA and protein levels, indicating that EGFR is a downstream target of USP39.

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We hypothesized that USP39 could up-regulate EGFR by increasing the pre-mRNA splicing.
USP39 increases the amount of EGFR.
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USP39 increases the amount of EGFR. 2 / 3
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Silencing of USP39 inhibited the expression of EGFR 3 '-end, and presented a remarkable block to the maturation of EGFR mRNA, suggesting that silencing of USP39 decreased the transcriptional elongation and maturation of EGFR mRNA.

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Microarray analysis suggested that knockdown of USP39 caused a reduced expression of EGFR.
Modified USP39 increases the amount of EGFR. 1 / 1
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Consistently, overexpression of USP39 upregulated EGFR expression both in both mRNA levels (PC-3 :P = 0.0258; DU145 :P = 0.0426) and protein levels.
USP39 decreases the amount of EGFR.
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USP39 decreases the amount of EGFR. 1 / 2
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Knockdown of USP39 downregulated EGFR expression in PC-3 and DU145 cells in mRNA (P < 0.0001 and P < 0.0001, respectively) and protein levels.
USP39 affects cell growth
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USP39 inhibits cell growth.
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In melanoma, knockdown USP39 inhibited cell growth and induced cell cycle arrest and apoptosis ( xref ).

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Depletion of USP39 by siRNA significantly suppressed cell growth and decreased invasive capacity of RCC cells.

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Previous studies found that down-regulation of USP39 could inhibit cell growth and colony formation of human breast cancer cells [XREF_BIBR].

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USP39 knockdown inhibited cell proliferation and colony formation in vitro in the HepG2 cells, while upregulation of USP39 promoted tumor cell growth.

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Recently, scientists reported aberrant USP39 expression could inhibit breast cancer cell growth in vitro [XREF_BIBR], however, little is known about how USP39 functions in human osteosarcoma and whether it can be used as an potential therapeutic target.
USP39 activates cell growth.
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In melanoma, knockdown USP39 inhibited cell growth and induced cell cycle arrest and apoptosis.

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These findings are in agreement with cell growth inhibition, which suggest that USP39 could modulate osteosarcoma cell growth via cell cycle control.

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In conclusion, knockdown of USP39 by RNAi inhibited cell growth due to inactivation of the CDK1 and CyclinB complex.

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In osteosarcoma cells, a decreased USP39 expression inhibited cell growth and induced apoptosis.

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In conclusion, the inhibition of USP39 in CAL27 cells suppressed cell growth probably via induction cell cycle arrest and apoptosis.
USP39 affects TP53
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USP39 inhibits TP53.
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USP39 inhibits TP53. 7 / 7
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Moreover, depletion of USP39 blocked activation of Akt, mTOR, p53, and PARP signaling pathways.

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USP39 attenuates the antitumor activity of cisplatin on colon cancer cells dependent on p53.

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Further studies demonstrated that depletion of USP39 results in an upregulation of p53 through prolonging its half-life and activating its transcriptional activation activity .

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Meanwhile, we found that USP39 knockdown also activates the p53 pathway, upregulation of p53, p-p53 (S15), p21 and BAX in HCC827 cells.

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on A549 cells to confirm the key role of p53, the WB result demonstrated that exposure to PFT-alpha (30 or 40 mum/48 h) clearly inhibited the p53 pathway activation, which activated by USP39 knockdown in A549 cells.

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Furthermore, USP39 knockdown increased the stability of the p53 protein by prolonging its half-life.

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Altogether, these results suggest that USP39 knockdown causes a significant accumulation of p53 via regulating both transcriptional levels and post-translational modifications of p53.
USP39 activates TP53.
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USP39 activates TP53. 2 / 3
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The underlying mechanism is demonstrated by knocking down USP39, that results in p53 upregulation, associated with its prolonged half-life.

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In addition, by employing a double luciferase reporter system assay, we found that depletion of USP39 enhances p53 responsive transcriptional reporter activity.
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For instance, USP39 promotes colorectal cancer growth and metastasis through the Wnt and beta-catenin pathway [XREF_BIBR].

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Thus, depletion of USP39 could inhibit the proliferation and metastasis of HCC cells.
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The depletion of USP39 could inhibit the proliferation and metastasis of HCC cells [11].
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Together, these data demonstrate that USP39 knockdown inhibits the metastasis of lung cancer cells in vivo and in vitro.

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USP39 promotes colorectal cancer growth and metastasis through the Wnt and beta-catenin pathway.
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Moreover, USP39 depletion inhibits HCC cell proliferation and metastasis by promoting ZEB1 degradation.

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Knocking down USP39 Inhibits the Growth and Metastasis of Non-Small-Cell Lung Cancer Cells through Activating the p53 Pathway.
MYC affects USP39
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MYC increases the amount of USP39.
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MYC increases the amount of USP39. 3 / 3
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In contrast, inhibition of c-MYC by shRNA decreased USP39 expression.

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As expected, overexpression of c-MYC significantly increased USP39 expression at both the RNA and protein level.

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C-MYC activates the transcription of USP39 in ovarian cancer cells.
MYC activates USP39.
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MYC activates USP39. 3 / 3
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In contrast , inhibition of c-MYC by shRNA decreased USP39 expression ( Fig. 4A-B ) .

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Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells.

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The effect of c-MYC on USP39 expression was further investigated by performing a luciferase assay, and the result showed that forced expression of c-MYC increased luciferase activity of the USP39 promoter reporter containing the wild-type but not the mutant c-MYC binding site.
Bisphenol A affects USP39
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Bisphenol A decreases the amount of USP39.
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Bisphenol A decreases the amount of USP39. 3 / 3
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Bisphenol A increases the amount of USP39.
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Bisphenol A increases the amount of USP39. 1 / 1
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USP39 affects Thr-Thr
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USP39 inhibits Thr-Thr.
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This indicates that USP39 shRNA could strongly block (p < 0.01) the cell cycle progression of TT cells.

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Knockdown of USP39 significantly inhibited proliferation of TT cells in vitro.
USP39 activates Thr-Thr.
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USP39 activates Thr-Thr. 2 / 2
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Taken together, these results suggest that knockdown of USP39 could inhibit TT cell proliferation by inducing G2/M phase cell cycle arrest.

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This indicates that knockdown of USP39 could strongly decrease the proliferation of TT cells.
USP39 affects RB1
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USP39 activates RB1.
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USP39 activates RB1. 3 / 3
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It showed that the down-regulation of USP39 gene can cause rb1 mRNA splicing abnormalities, which then leaded to downstream target genes e2f4 up-regulated in zebrafish.

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We then performed an rb1 mRNA overexpression experiment in usp39 mutants and observed partial rescue of the adenohypophysis phenotype (XREF_FIG, mutant N = 34, ~ 50% showed rescue), validating the importance of usp39 mediated rb1 mRNA splicing in controlling pituitary lineage expansion during development.

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Our studies reveal a novel role of usp39 mediated mRNA splicing of rb1 in pituitary cell growth control, which is critical for maintaining embryonic pituitary homeostasis.
USP39 inhibits RB1.
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USP39 inhibits RB1. 1 / 1
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Silencing of USP39 could specifically reduce the Aurora B mRNA expression [XREF_BIBR], and mutation of zebrafish USP39 induces rb1 splicing defects and pituitary lineage expansion [XREF_BIBR].
USP39 affects Neoplasms
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USP39 activates Neoplasms.
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USP39 promotes tumor progression by increasing HMGA2 levels in ovarian cancer cells .

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USP39 depletion led to reduced tumor mass and volume ( Fig. 3B ) .

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USP39 promotes tumor progression by increasing HMGA2 levels in ovarian cancer cells We next investigated the functional significance of the USP39-HMGA2 axis .
USP39 inhibits Neoplasms.
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Knockdown of USP39 could inhibit the proliferation and induce apoptosis of SMMC-7721 cells, as well as the growth of xenograft tumors in nude mice.
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USP39 affects CDKN1A
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USP39 inhibits CDKN1A.
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USP39 inhibits CDKN1A. 2 / 2
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Meanwhile, we found that USP39 knockdown also activates the p53 pathway, upregulation of p53, p-p53 (S15), p21 and BAX in HCC827 cells.

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However, treated with PFT-alpha reduced the up-regulation of p21 and BAX induced by USP39 knockdown, but had no effect on the down-regulation of cell cycle related proteins (CDK1 and CyclinB1 and CDK2 and CyclinA2) induced by USP39 knockdown.
USP39 increases the amount of CDKN1A.
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Mutated USP39 increases the amount of CDKN1A. 1 / 1
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Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression.
USP39 activates CDKN1A.
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USP39 activates CDKN1A. 1 / 1
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USP39 mediates p21 dependent proliferation and neoplasia of colon cancer cells by regulating the p53/p21/CDC2/cyclin B1 axis.
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Third, we demonstrated that USP39 knockdown inhibits cell migration and invasion by upregulating p53 and the downstream proteins MMP2 and MMP9 [XREF_BIBR].

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Third , we demonstrated that USP39 knockdown inhibits cell migration and invasion by upregulating p53 and the downstream proteins MMP2 and MMP9 [ 31 ] .

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As shown in XREF_FIG A-F, USP39 knockdown reduced the cell migration and invasion of both USP39KD cells in comparison to the control cells (* p < 0.05, ** p < 0.01, **** p < 0.0001).
USP39 affects Interferon
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Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK and STAT downstream of type I signaling by enhancing IFN stimulated response elements promoter activity and expression of IFN stimulated genes.

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Intriguingly, USP39 promotes IFN-mediated antiviral responses by decreasing K6-linked but not canonical K48-linked polyubiquitination of STAT1 for degradation (118), eventhough K6-linked ubiquitin chains are often related to DNA damage instead of protein degradation (142).

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Unlike USP2A, the deubiquitinating enzymes BRCC36, USP13, and USP39 positively regulate IFN activities by attenuating the polyubiquitination level of STAT1, and this process is independent of IFN treatment, which suggests divergent functional roles of these DUBs under differential contexts.Additionally, ATXN3 does not affect IFN-I production during viral infection but positively regulates IFNAR1-mediated downstream signaling by targeting HDAC3 (108).
USP39 affects FAM126A
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USP39 activates FAM126A. 3 / 3
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The depletion of USP39 could inhibit the proliferation and metastasis of HCC cells [11].
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The mRNA level of USP39 was significantly elevated in HCC.
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Thus, depletion of USP39 could inhibit the proliferation and metastasis of HCC cells.
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USP39 affects CDK4
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USP39 decreases the amount of CDK4.
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USP39 decreases the amount of CDK4. 2 / 2
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Knockdown of USP39 in VSMCs inhibited cyclinD1 and CDK4 protein expression compared with transfection with control siRNA (XREF_FIG), which are essential proteins for G1/S phase transformation.

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Knockdown of USP39 inhibits VSMC proliferation and the expression of cyclin D1 and CDK4.
USP39 increases the amount of CDK4.
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USP39 increases the amount of CDK4. 1 / 1
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Furthermore, knockdown of USP39 inhibited VSMC cell proliferation and the expression of cyclin D1 and cyclin dependent kinase 4, as analyzed via cell counting, MTT assay and western blotting.
E2F4 affects USP39
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E2F4 activates USP39.
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E2F4 activates mutated USP39. 2 / 2
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In addition, we performed quantitative RT-PCR analysis on the rb1 mRNA injected usp39 embryos and observed a 30% reduction of e2f4 expression compared to control uninjected usp39 mutants (XREF_SUPPLEMENTARY), indicating that e2f4 upregulation in usp39 mutant is secondary to Rb1 loss of function.

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Consequently, e2f4 upregulation in usp39 mutants may contribute to increased proliferation of terminally differentiated pituitary cells leading to lineage expansion as seen in our BrdU studies (XREF_SUPPLEMENTARY).
E2F4 inhibits USP39.
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E2F4 inhibits mutated USP39. 1 / 1
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In addition, knockdown of e2f4 partially rescued pomc lineage expansion in usp39 mutants.
Methyl methanesulfonate increases the amount of USP39. 2 / 2
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USP39 affects carboplatin
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USP39 promotes ovarian cancer malignant phenotypes and carboplatin chemoresistance.

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Another member of the USP family, USP39, was reported to promote OC malignant phenotypes and carboplatin chemoresistance.
USP39 affects PARP1
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USP39 inhibits PARP1. 1 / 2
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Moreover, depletion of USP39 blocked activation of Akt, mTOR, p53, and PARP signaling pathways.
USP39 affects FOXM1
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USP39 activates FOXM1. 2 / 2
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The results suggest that knockdown of USP39 inhibits the growth of HCC in vitro and in vivo, potentially through the induction of G2/M arrest by regulating the pre-mRNA splicing of FoxM1.

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Inhibition of USP39 by siRNA has downregulated FOXM1 and in turn led to tumor volume reduction in xenograft model of HCC.
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USP39 promotes tumorigenesis by stabilizing and deubiquitinating SP1 protein in hepatocellular carcinoma .

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Furthermore , our study adds ESCC to the list of cancers where USP39 contributes to tumorigenesis and progression .
USP39 affects BAX
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USP39 inhibits BAX. 2 / 2
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Meanwhile, we found that USP39 knockdown also activates the p53 pathway, upregulation of p53, p-p53 (S15), p21 and BAX in HCC827 cells.

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However, treated with PFT-alpha reduced the up-regulation of p21 and BAX induced by USP39 knockdown, but had no effect on the down-regulation of cell cycle related proteins (CDK1 and CyclinB1 and CDK2 and CyclinA2) induced by USP39 knockdown.
USP39 affects AKT
| 2
USP39 inhibits AKT. 2 / 2
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Mechanistically, downregulation of USP39 blocked the activation of Akt and extracellular signal regulated kinase signaling pathways in RCC cells.

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Moreover, depletion of USP39 blocked activation of Akt, mTOR, p53, and PARP signaling pathways.
EGFR affects USP39
| 2
EGFR activates USP39. 2 / 2
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To verify whether the regulatory effect of USP39 was EGFR specific, ectopic expression of USP39 were performed in PC-3 and DU145 cells, which showed that overexpressed USP39 upregulated EGFR mRNA and protein levels, indicating that EGFR is a downstream target of USP39.

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EGFR is a downstream target of USP39.

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Knockdown of USP39 inhibits malignant transformation of PCa through interrupting the transcription elongation, maturation and stability of EGFR mRNA.

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Here we identified that USP39 promoted tumorigenesis of PCa through activating EGFR pathway.
USP39 affects cytokinesis
| 2
USP39 inhibits cytokinesis.
| 1
| 1

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A previous study indicated that USP39 silencing induced defective chromosome segregation and cytokinesis in U2OS cells, indicating USP39 is critical in the regulation of mitosis.
USP39 activates cytokinesis.
| 1
| 1

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As a confirmed spliceosome factor, USP39 is critical to maintain the spindle checkpoint and promote successful cytokinesis through the regulation of Aurora B mRNA splicing in mammalian cells.
USP39 affects CDK1
| 2
USP39 inhibits CDK1.
| 1
USP39 inhibits CDK1. 1 / 1
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However, treated with PFT-alpha reduced the up-regulation of p21 and BAX induced by USP39 knockdown, but had no effect on the down-regulation of cell cycle related proteins (CDK1 and CyclinB1 and CDK2 and CyclinA2) induced by USP39 knockdown.
USP39 increases the amount of CDK1.
| 1
USP39 increases the amount of CDK1. 1 / 1
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Besides, both the phosphorylated and basal levels of CDK1 were reduced by USP39 knockdown.
USP39 affects ADAM9
| 2
USP39 increases the amount of ADAM9.
| 1
USP39 increases the amount of ADAM9. 1 / 1
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Altogether, our data shows that USP39 induces mRNA maturation and elevates the expression of ADAM9 in glioma cells and may thus be considered as potential target for treating patients with glioma.
USP39 activates ADAM9.
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USP39 activates ADAM9. 1 / 1
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Further on, USP39 induced ADAM9 mRNA maturation and decreased the expression of integrin beta1.
Trimellitic anhydride increases the amount of USP39. 1 / 1
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ctd
No evidence text available
Tetrachloromethane increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Sodium arsenite increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Sodium arsenate increases the amount of USP39. 1 / 1
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ctd
No evidence text available

sparser
Inhibition of USP39 by siRNA has downregulated FOXM1 and in turn led to tumor volume reduction in xenograft model of HCC ( xref ).
| 1

sparser
Therefore, the inhibition of USP39 by shRNA might be a potential therapeutic method in MTC.
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Pirinixic acid decreases the amount of USP39. 1 / 1
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ctd
No evidence text available
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ctd
No evidence text available
Nimesulide affects USP39
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Nimesulide increases the amount of USP39. 1 / 1
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ctd
No evidence text available
Nefazodone affects USP39
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Nefazodone increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Methamphetamine increases the amount of USP39. 1 / 1
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ctd
No evidence text available
Mercury(0) affects USP39
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Mercury(0) increases the amount of USP39. 1 / 1
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ctd
No evidence text available
Lead atom affects USP39
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Lead atom decreases the amount of USP39. 1 / 1
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ctd
No evidence text available
Indometacin affects USP39
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Indometacin increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Hydroperoxide increases the amount of USP39. 1 / 1
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ctd
No evidence text available
1 |
Hsa-miR-193b-3p decreases the amount of USP39. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
Glyphosate affects USP39
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Glyphosate increases the amount of USP39. 1 / 1
1 |

ctd
No evidence text available
Gentamycin affects USP39
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Gentamycin increases the amount of USP39. 1 / 1
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ctd
No evidence text available
Flutamide affects USP39
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Flutamide increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Dexamethasone increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Carbon nanotube increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Cadmium atom decreases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Benzo[a]pyrene increases the amount of USP39. 1 / 1
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ctd
No evidence text available
All-trans-retinoic acid decreases the amount of USP39. 1 / 1
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ctd
No evidence text available
Acrylamide affects USP39
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Acrylamide increases the amount of USP39. 1 / 1
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ctd
No evidence text available
Abrine affects USP39
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Abrine increases the amount of USP39. 1 / 1
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ctd
No evidence text available
USP39 affects volume
| 1
USP39 activates volume. 1 / 1
| 1

eidos
USP39 depletion led to reduced tumor mass and volume ( Fig. 3B ) .

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The results demonstrated that the level of the 3 '-end of EGFR decreased (P = 0.0015) more sharply than that of the 5 '-end (P = 0.0069), and the ratio ofthe 3 '-end to 5 '-end levels was significant decreased (P = 0.0297), implying that knockdown of USP39 might inhibit the transcription elongation of EGFR, and might produce unstable EGFR mRNA fragments lacking the 3 '-UTR.
| 1

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In yeast, the ABH1 homolog CBP80 and the SAD1 homolog Lsm5 are active components of the spliceosome and mediate various steps of RNA metabolism [47], but these two proteins do not seem to interact dir[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
| 1

eidos
Altogether , our data shows that USP39 induces mRNA maturation and elevates the expression of ADAM9 in glioma cells and may thus be considered as potential target for treating patients with glioma .
USP39 affects growth
| 1
USP39 inhibits growth. 1 / 1
| 1

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Knocking down USP39 Inhibits the Growth and Metastasis of Non-Small-Cell Lung Cancer Cells through Activating the p53 Pathway.

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A previous study indicated that USP39 silencing induced defective chromosome segregation and cytokinesis in U2OS cells, indicating USP39 is critical in the regulation of mitosis.
USP39 affects cell death
| 1
| 1

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Knockdown of SF3B1, PRPF8, UBL5 and USP39 increased cell death in all cSCC cell lines.
| 1
| 1

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USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1.
USP39 affects ZEB1
| 1
USP39 activates ZEB1. 1 / 1
| 1

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Moreover, USP39 depletion inhibits HCC cell proliferation and metastasis by promoting ZEB1 degradation.
USP39 affects VEGFA
| 1
USP39 decreases the amount of VEGFA. 1 / 1
| 1

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USP39 knockdown upregulated the expression of VEGF-A 165b , and USP39 overexpression downregulated the expression of VEGF-A 165b significantly (both P < 0.05).
USP39 affects TAZ
| 1
USP39 activates TAZ. 1 / 1
| 1

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Finally, loss of USP39 decreased TAZ pre-mRNA splicing efficiency in glioma cells in vitro, which led to reduced levels of TAZ protein.
| 1
| 1

eidos
To test whether USP39 modulate spliceosome activity via SF3B1 , we measured phosphorylated SF3B1 in ovarian cancer cells with USP39 overexpression or knockdown .
USP39 affects STAT
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USP39 activates STAT. 1 / 1
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Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK and STAT downstream of type I signaling by enhancing IFN stimulated response elements promoter activity and expression of IFN stimulated genes.
USP39 affects RCC
| 1
USP39 inhibits RCC. 1 / 1
| 1

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Depletion of USP39 by siRNA significantly suppressed cell growth and decreased invasive capacity of RCC cells.
USP39 affects MTOR
| 1
USP39 inhibits MTOR. 1 / 1
| 1

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Moreover, depletion of USP39 blocked activation of Akt, mTOR, p53, and PARP signaling pathways.
USP39 affects JAK
| 1
USP39 activates JAK. 1 / 1
| 1

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Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK and STAT downstream of type I signaling by enhancing IFN stimulated response elements promoter activity and expression of IFN stimulated genes.
USP39 affects Integrins
| 1
USP39 decreases the amount of Integrins. 1 / 1
| 1

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Further on, USP39 induced ADAM9 mRNA maturation and decreased the expression of integrin beta1.
USP39 affects ITGB1
| 1
USP39 inhibits ITGB1. 1 / 1
| 1

eidos
Further on , USP39 induced ADAM9 mRNA maturation and decreased the expression of integrin beta1 .
USP39 affects Half-Life
| 1
| 1

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We observe that USP39 stabilizes SP1 protein and prolongs its half-life by promoting its deubiquitylation pathway .
USP39 affects HMGA2
| 1
USP39 increases the amount of HMGA2. 1 / 1
| 1

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Ectopic expression of USP39 increased the mRNA and protein levels of HMGA2, whereas USP39 knockdown had the opposite effect.
USP39 affects ERK
| 1
USP39 inhibits ERK. 1 / 1
| 1

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Mechanistically, downregulation of USP39 blocked the activation of Akt and extracellular signal regulated kinase signaling pathways in RCC cells.

reach
The depletion of USP39 has been found to cause activation of the p53 signaling pathway, an important regulatory mechanism in cell cycle and DNA replication, by stabilizing the p53 target p21 in multiple kinds of cancer cell lines [23, 26, 27].
| PMC
USP39 affects Cyclin
| 1
USP39 decreases the amount of Cyclin. 1 / 1
| 1

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Knockdown of USP39 inhibits VSMC proliferation and the expression of cyclin D1 and CDK4.
| 1

eidos
Previously , USP39 depletion was found to cause a significant reduction in pre-mRNA splicing efficiency in colon cancer and glioma25 ,30 .

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USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1.
USP39 affects CYCD1-1
| 1
USP39 decreases the amount of CYCD1-1. 1 / 1
| 1

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Knockdown of USP39 in VSMCs inhibited cyclinD1 and CDK4 protein expression compared with transfection with control siRNA (XREF_FIG), which are essential proteins for G1/S phase transformation.
USP39 affects CDK2
| 1
USP39 inhibits CDK2. 1 / 1
| 1

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However, treated with PFT-alpha reduced the up-regulation of p21 and BAX induced by USP39 knockdown, but had no effect on the down-regulation of cell cycle related proteins (CDK1 and CyclinB1 and CDK2 and CyclinA2) induced by USP39 knockdown.
USP39 affects CCNB1
| 1
USP39 activates CCNB1. 1 / 1
| 1

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USP39 mediates p21 dependent proliferation and neoplasia of colon cancer cells by regulating the p53/p21/CDC2/cyclin B1 axis.
USP39 affects CCNA2
| 1
USP39 inhibits CCNA2. 1 / 1
| 1

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However, treated with PFT-alpha reduced the up-regulation of p21 and BAX induced by USP39 knockdown, but had no effect on the down-regulation of cell cycle related proteins (CDK1 and CyclinB1 and CDK2 and CyclinA2) induced by USP39 knockdown.
Surface-Active Agents increases the amount of USP39. 1 / 1
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ctd
No evidence text available
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Plant Extracts increases the amount of USP39. 1 / 1
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ctd
No evidence text available
PRH2 affects USP39
| 1
PRH2 activates USP39. 1 / 1
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Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells.
POMC affects USP39
| 1
POMC activates mutated USP39. 1 / 1
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Furthermore, injection of mRNA encoding wild-type usp39 rescued the mutant phenotype (XREF_TABLE), indicating that pituitary pomc upregulation in usp39 mutants results from the nonsense mutation in zebrafish usp39.
PAX4 affects USP39
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PAX4 decreases the amount of USP39. 1 / 1
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biopax:msigdb
No evidence text available
N-methyl-4-phenylpyridinium increases the amount of USP39. 1 / 1
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ctd
No evidence text available
MLN7243 affects USP39
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MLN7243 desumoylates USP39. 1 / 1
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ctd
No evidence text available
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ctd
No evidence text available
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ctd
No evidence text available
17alpha-ethynylestradiol increases the amount of USP39. 1 / 1
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ctd
No evidence text available