USP27X Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 27 X-linked
HGNC Gene Symbol
USP27X
Identifiers
hgnc:13486 NCBIGene:389856 uniprot:A6NNY8
Orthologs
mgi:1859645 rgd:1564628
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP27X
Number of Papers
17 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

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP27Xusing 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 USP27X using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
G0S2 G0/G1 switch 2 -5.37e-01 4.14e-08 9.13e-04

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 USP27X 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
USP27X deubiquitinates Histone_H2B. 2 / 2
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The requirement of ATXN7L3 for H2B deubiquitination by USP22, USP27x, and USP51 suggests that the ATXN7L3 zinc finger plays a role analogous to that of the Sgf11 zinc finger in docking human SAGA DUB [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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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.
USP27X leads to the deubiquitination of BCL2L11. 2 / 2
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Here, we report the identification of a deubiquitinase, Usp27x, that binds Bim upon its ERK-dependent phosphorylation and can upregulate its expression levels.

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Thus, Usp27x can trigger via its proteolytic activity the deubiquitination of Bim and enhance its levels, counteracting the anti-apoptotic effects of ERK activity, and therefore acts as a tumour suppressor.
USP27X deubiquitinates Cyclin_E. 2 / 2
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The observation that USP27 interacts with and deubiquitinates Cyclin E led us to think that USP27 might involve in cell cycle progression by regulating Cyclin E stability.

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First, USP27 interacts with and colocalizes with Cyclin E. Second, USP27 negatively regulates Cyclin E ubiquitination.
USP27X leads to the deubiquitination of DDX58. 1 / 1
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Additionally, ubiquitination assays demonstrated that USP27X reduced RIG-I ubiquitination, specifically the K63-ubiquitin linkage type.
USP27X deubiquitinates HES1. 1 / 1
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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.
USP27X deubiquitinates H2BC10. 1 / 1
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In contrast, depletion of non-enzymatic components, ATXN7L3 or ENY2, results in increased H2Bub1. These observations led us to discover two H2Bub1 DUBs, USP27X and USP51, which function independently of SAGA and compete with USP22 for ATXN7L3 and ENY2 for activity.
Modified USP27X leads to the deubiquitination of BCL2L11. 1 / 1
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Overexpression of Usp27x reduces ERK dependent Bim ubiquitination, stabilizes phosphorylated Bim, and induces apoptosis in PMA stimulated cells, as well as in tumour cells with a constitutively active Raf and ERK pathway.
USP27X deubiquitinates CGAS. 1 / 1
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Cutting Edge : USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA Mediated Signaling.
USP27X deubiquitinates GATD3B. 1 / 1
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We found that Hes1 was deubiquitinated and stabilized by Usp27x and its homologs ubiquitin specific protease 22 (Usp22) and ubiquitin specific protease 51 (Usp51).

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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Importantly, expression of WT, but not mutant USP27X, prevented the proliferation defects caused by depletion of endogenous USP27X (XREF_FIG).

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Importantly, expression of WT, but not mutant USP27X, prevented the proliferation defects caused by depletion of endogenous USP27X.

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Expression of WT-USP27X on its own led to slightly increased proliferation, whereas expression of the C285S mutant led to slightly reduced proliferation.

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Our data showed that USP27 promotes cell proliferation and migration.

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The observation that USP27 promotes cell cycle progression and cell proliferation prompted us to imagine that depletion of USP27 expression might suppress tumor progression.

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Herein, we demonstrate that USP27 regulates Cyclin E abundance to accelerate cell cycle progression, cell proliferation, and tumor cell growth as well.

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Furthermore, cell proliferation was also remarkably reduced in the combination of USP27 knockdown and 5-FU treatment, whereas overexpression of USP27 or addition of Cyclin E in USP27 knockdown cells could raise cell proliferation.

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Importantly, expression of WT, but not mutant USP27X, prevented the proliferation defects caused by depletion of endogenous USP27X (XREF_FIG).

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Importantly, expression of WT, but not mutant USP27X, prevented the proliferation defects caused by depletion of endogenous USP27X.
USP27X affects Cyclin_E
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USP27X activates Cyclin_E.
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USP27 mediated Cyclin E stabilization drives cell cycle progression and hepatocellular tumorigenesis.

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XREF_FIG, catalytically inactive USP27/CA mutant failed to protect Cyclin E from degradation, implying that the DUB activity is required for USP27 mediated Cyclin E stabilization.

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USP27 mediated Cyclin E stabilization is involved in tumorigenesis, suggesting that targeting USP27 may represent a new therapeutic strategy to treat cancers with aberrant overexpression of Cyclin E protein.

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XREF_FIG, MG132 (proteasome inhibitor) treatment could rescue the USP27 knockdown mediated degradation of Cyclin E protein.

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Finally, we determined whether USP27 mediated Cyclin E stability is through proteasome.

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Our discovery that USP27 mediated Cyclin E stabilization implied that USP27 might modulate cell cycle and cell proliferation through Cyclin E regulation.
USP27X increases the amount of Cyclin_E.
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USP27X increases the amount of Cyclin_E. 1 / 1
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Third, USP27 positively regulates Cyclin E protein level.
USP27X affects cell cycle
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We found that USP27 knockdown suppresses cell cycle progression by increasing the percentage of cells in G0/G1 phase, which can be reversed by the addition of Cyclin E expression.

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Herein, we demonstrate that USP27 regulates Cyclin E abundance to accelerate cell cycle progression, cell proliferation, and tumor cell growth as well.

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The observation that USP27 promotes cell cycle progression and cell proliferation prompted us to imagine that depletion of USP27 expression might suppress tumor progression.

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To further support our notion that USP27 promotes cell cycle progression, we detected a statistically significant reduction in the growth of Hep3B and MHCC97H cells compared with that of control cells with single stable knockdown of USP27.

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XREF_FIG, USP27 knockdown suppresses cell cycle progression by increasing the percentage of cells in G1/S phase but decreasing the percentage of cells in G2/M phase, similar to 5-FU treatment.
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USP27X can also deubiquitinate and stabilize Snail1 when induced by TGF-beta and therefore promotes EMT and tumor metastasis [ 53 ] .

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Taken together, these results suggested that USP27 might promote hepatoma metastasis.

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Although Cyclin E has been reported to involve in metastasis [XREF_BIBR], how USP27 promotes migration and metastasis also need further detailed exploration.

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How does USP27 promote migration and metastasis?
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Down regulation of USP27 suppresses hepatocellular migration and metastasis.
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Finally, deletion of Usp27x reduces apoptosis in NSCLC cells treated with an EGFR inhibitor.

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The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis.

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Overexpression of Usp27x induces low levels of apoptosis in melanoma and non small cell lung cancer (NSCLC) cells and substantially enhances apoptosis induced in these cells by the inhibition of ERK signalling.
Modified USP27X activates apoptotic process. 1 / 1
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Overexpression of Usp27x reduces ERK dependent Bim ubiquitination, stabilizes phosphorylated Bim, and induces apoptosis in PMA stimulated cells, as well as in tumour cells with a constitutively active Raf and ERK pathway.
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In addition, in NSCLC cells, depletion of USP27x reduces apoptosis when treated with an EGFR inhibitor.
TGFB affects USP27X
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TGFB activates USP27X. 4 / 4
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TGFbeta also induces USP27X expression , which increases SNAI1 stability by deubiquitination [ 55 ] .
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USP27X can also deubiquitinate and stabilize Snail1 when induced by TGF-beta and therefore promotes EMT and tumor metastasis [ 53 ] .

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TGFbeta activated USP27X deubiquitinase regulates cell migration and chemoresistance via stabilization of Snail1.

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USP27X was upregulated by TGFbeta during EMT and was required for TGFbeta induced expression of Snail1 and other mesenchymal markers in epithelial cells and CAF.
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.
USP22 activates USP27X.
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USP22 activates USP27X. 2 / 2
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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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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.
USP27X affects BCL2L11
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USP27x DUB antagonizes the Raf-ERK Bim degradation pathway thus stabilizing Bim expression.

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Cathepsin K inhibition induced mitochondrial ROS enhances sensitivity of cancer cells to anti-cancer drugs through USP27x mediated Bim protein stabilization.

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Loss of endogenous Usp27x enhances the Bim degrading activity of oncogenic Raf.
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Valproic acid decreases the amount of USP27X. 2 / 2
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No evidence text available

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No evidence text available
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Hsa-miR-8485 decreases the amount of USP27X. 2 / 2
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No evidence text available

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No evidence text available
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Hsa-miR-552-5p decreases the amount of USP27X. 2 / 2
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No evidence text available

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Hsa-miR-302c-5p decreases the amount of USP27X. 2 / 2
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No evidence text available

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Benzo[a]pyrene decreases the amount of USP27X. 2 / 2
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No evidence text available

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No evidence text available

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USP27X modulates tumor chemoresistance and invasion through deubiquitination and stabilization of Snail1 XREF_BIBR.

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Conversely, overexpression of USP27 evidently enhanced cell invasion.
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Bisphenol A increases the amount of USP27X.
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Bisphenol A increases the amount of USP27X. 1 / 1
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No evidence text available
Bisphenol A decreases the amount of USP27X.
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Bisphenol A decreases the amount of USP27X. 1 / 1
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No evidence text available
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In our study, we found that both USP27 and Cyclin E are downregulated by 5-FU treatment in a dose dependent manner.
5-formyluracil decreases the amount of USP27X.
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5-formyluracil decreases the amount of USP27X. 1 / 1
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Anti-cancer drug 5-FU regulates cell cycle progression and inhibits hepatocellular proliferation by downregulating USP27 expression.
Urethane affects USP27X
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Urethane decreases the amount of USP27X. 1 / 1
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No evidence text available
Superoxide affects USP27X
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Down-regulation of Raptor expression increased mitochondrial ROS production, and mitochondria specific superoxide scavengers prevented USP27x mediated stabilization of Bim by inhibition of Cat K. Moreover, combined treatment with Cat K inhibitor (odanacatib) and tumor necrosis factor related apoptosis inducing ligand (TRAIL) reduced tumor growth and induced cell death in a xenograft model.
Sunitinib affects USP27X
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Sunitinib decreases the amount of USP27X. 1 / 1
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No evidence text available
Silver(0) affects USP27X
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Silver(0) decreases the amount of USP27X. 1 / 1
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No evidence text available
Potassium dichromate increases the amount of USP27X. 1 / 1
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No evidence text available
Jinfukang affects USP27X
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Jinfukang increases the amount of USP27X. 1 / 1
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No evidence text available
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Hsa-miR-603 decreases the amount of USP27X. 1 / 1
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No evidence text available
Dieldrin affects USP27X
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Dieldrin increases the amount of USP27X. 1 / 1
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Dibutyl phthalate decreases the amount of USP27X. 1 / 1
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No evidence text available
Cisplatin affects USP27X
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Cisplatin increases the amount of USP27X. 1 / 1
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No evidence text available

eidos
USP27X can also deubiquitinate and stabilize Snail1 when induced by TGF-beta and therefore promotes EMT and tumor metastasis [ 53 ] .
USP27X affects cisplatin
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USP27X depletion impaired Snail1 dependent cell migration and invasion and metastasis formation and increased cellular sensitivity to cisplatin.
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As shown in Figure S5A-D, depletion of USP27 expression significantly decreased cell migration compared with the control in Hep3B and MHCC97H cells using wound healing assay.
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Herein, we demonstrate that USP27 regulates Cyclin E abundance to accelerate cell cycle progression, cell proliferation, and tumor cell growth as well.

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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.
USP27X affects Ubiquitin
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In the past year, two other deubiquitinating enzymes, USP27X and USP1, have been reported to impede ubiquitin mediated degradation of Snail1 in various biological contexts XREF_BIBR, XREF_BIBR.
USP27X affects RNF168
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USP27X activates RNF168. 1 / 1
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Interestingly, the DUBs USP26 and USP27 were found to modulate RNF168 mediated protein ubiquitylation at DSB sites, preventing excessive spreading of RAP80-BRCA1, promoting association of BRCA1 with P[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP27X affects RAF
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USP27X inhibits RAF. 1 / 1
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Loss of endogenous Usp27x enhances the Bim degrading activity of oncogenic Raf.
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Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619.
USP27X affects Interferon
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Among the DUBs that interact with cGAS or MDA5, USP27X (98) and USP29 (99) stabilize cGAS and thus positively regulate IFN production and antiviral activities.
Soman affects USP27X
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Soman increases the amount of USP27X. 1 / 1
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No evidence text available
N-methyl-4-phenylpyridinium increases the amount of USP27X. 1 / 1
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No evidence text available
ENY2 affects USP27X
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ENY2 deubiquitinates USP27X. 1 / 1
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Our results now reveal that in addition to USP22, ATXN7L3 and ENY2 activate two previously uncharacterized deubiquitinating enzymes, USP27X and USP51, which are not part of SAGA.
Cyclin_E affects USP27X
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Interestingly, USP27 expression might also be regulated by Fbxw7, a well-known E3 ubiquitin ligase of Cyclin E, which interacts with and degrades USP27.
CAT affects USP27X
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CAT decreases the amount of USP27X. 1 / 1
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Inhibition of Cat K increased USP27x expression, and knock down of USP27x markedly blocked Cat K induced up-regulation of Bim expression.
ATXN7L3 affects USP27X
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ATXN7L3 deubiquitinates USP27X. 1 / 1
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Our results now reveal that in addition to USP22, ATXN7L3 and ENY2 activate two previously uncharacterized deubiquitinating enzymes, USP27X and USP51, which are not part of SAGA.
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ctd
No evidence text available