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.
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
Literature Mining
INDRA was used to automatically assemble known mechanisms
related to USP17L2 from literature and knowledge bases.
The first section shows only DUB activity and the second shows all other results.
Based on these genomic data and our finding that NCOR2 represses DUB3 expression in cultured cells, we hypothesized that loss of NCOR due to deletions or mutations results in DUB3 upregulation, which [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Knockdown of DUB3 completely abolished NCOR2-depletion-induced elevation of BRD4 protein and BRD4 protein polyubiquitination but had no effect on BRD4 mRNA expression.
Furthermore, PD0332991 treatment also increased BRD4 polyubiquitination, shortened the BRD4 protein half-life, and reversed DUB3 mediated deubiquitination of BRD4 in DU145 cells.
In support of these findings, we show that inhibition of BRD4 by JQ1 blocks NCOR2 mRNA expression, which in turn dismisses NCOR2 mediated repression of DUB3 and DUB3 mediated deubiquitination of BRD4.
In agreement with these findings, knockdown of DUB3 shortened the BRD4 protein half-life and dramatically increased endogenous BRD4 ubiquitination in PC-3 cells.
DUB3 and USP17 mediates deubiquitination of CDC25A, preventing CDC25A degradation by the proteasome during the G1/S and G2/M phases promoting cell-cycle progression [XREF_BIBR].
Dub3 knockdown in cells increased Cdc25A ubiquitylation and degradation, resulting in reduced Cdk and Cyclin activity and arrest at G1/S and G2/M phases of the cell cycle.
We previously reported that the USP17 deubiquitinating enzyme having hyaluronan binding motifs (HABMs) interacts with human SDS3 (suppressor of defective silencing 3) and specifically deubiquitinates Lys-63 branched polyubiquitination of SDS3 resulting in negative regulation of histone deacetylase (HDAC) activity in cancer cells.
In this study, we identified Dub3 as a novel DUB for both Slug and Twist. We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose-dependent manner, whereas Dub3-knockdown decreased their protein levels.
In this study, we identified Dub3 as a novel DUB for both Slug and Twist. We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose-dependent manner, whereas Dub3-knockdown decreased their protein levels.
Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124].
DUB-3 also influenced the Ras/MEK/ERK signaling pathway and deubiquitinated Ras converting enzyme 1 (RCE1), decreasing proliferation of cells [XREF_BIBR].
?Several DUBs were found to decrease the ubiquitination of 6myc-HAS2, among which, the most effective were USP17 and USP4. USP17 efficiently removed polyubiquitination, whereas USP4 preferentially removed monoubiquitination of 6myc-HAS2.
Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124].
Co-expression of wild-type (WT) Dub3 almost completely abolished ubiquitination of Slug and Twist, while co-expression of CS-Dub3 did not show this effect (lane 2 vs lane 3 in both upper panels, Figure XREF_FIG).
We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90伪 to subsequently promote pro-AEP intracellular stability as well as secretion.?
Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124].
Co-expression of wild-type (WT) Dub3 almost completely abolished ubiquitination of Slug and Twist, while co-expression of CS-Dub3 did not show this effect (lane 2 vs lane 3 in both upper panels, Figure XREF_FIG).
Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124].
Dub-3, which is known as Usp17, is responsible for the regulation of cell growth and survival, and the constitutive expression of Dub-3 can block cell proliferation XREF_BIBR - XREF_BIBR.
We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the ' CAAX ' box protease RCE1.
More recently, we have also reported that constitutive expression of DUB-3 can block cell proliferation [XREF_BIBR, XREF_BIBR] and subsequently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the ' CAAX ' box protease Ras converting enzyme 1 (RCE1) [XREF_BIBR].
In particular, DUB-1 expression results in cell cycle arrest prior to S-phase [XREF_BIBR], DUB-2 expression markedly inhibits apoptosis induced by cytokine withdrawal [XREF_BIBR] and we have previously reported that constitutive expression of DUB-3 blocks cell proliferation [XREF_BIBR, XREF_BIBR, XREF_BIBR] through its regulation of the ubiquitination and activity of the ' CAAX ' box protease RCE1 [XREF_BIBR, XREF_BIBR].
Finally, we have demonstrated that constitutive expression of DUB-3 blocks proliferation and can initiate apoptosis in both IL-3-dependent Ba/F3 cells and NIH3T3 fibroblasts.
USP17 subfamily members have been previously identified [XREF_BIBR] and one of them, DUB-3, has shown that the constitutive expression of DUB-3 blocks proliferation and can lead to apoptosis [XREF_BIBR].
In summary, we found that DUB3 enhanced OSCC cells proliferation and xenograft tumor growth, while inhibited their apoptosis via promoting BRD4 mediated upregulation of EZH2.
Similar to our observations, previous shRNA studies have also indicated that Dub3 knockdown reduces proliferation by inhibiting the G1-S phase cell cycle progression and inhibits chemotaxis [14,15,26][MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
McFarlane et al. identify that USP17 is highly expressed in several tumor biopsies , and USP17 depletion significantly impairs G1-S phase transition and blocks cell proliferation ( 56 ) .
We demonstrated that knockdown of endogenous DUB3 by two independent shRNAs largely decreased BRD4 protein and that these effects were reversed by restored expression of DUB3-WT and the phospho mimick[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
We further showed that forced expression of DUB3 induced upregulation of BRD4 proteins in cultured cells and that elevation of DUB3 expression was correlated with a high level of BRD4 protein in a sub[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Treatment of DU145 cells with PD0332991 decreased BRD4 protein levels in a time dependent manner, and the effect of PD0332991 was completely impeded by the proteasome inhibitor MG132, arguing that CDK[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
In contrast, knockdown of DUB3 by two independent shRNAs decreased the level of endogenous BRD4 proteins but had no overt effect on BRD4 mRNA expression in both PC-3 and DU145 cells.
Accordingly, overexpression of DUB3 increased the level of ectopically expressed full-length BRD4 protein in a dose dependent manner but had no effect on BRD4DeltaCTM mutant, BRD2 or BRD3 in PC-3 cell[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
To test this hypothesis, we co-expressed DUB3 with BRD4 in 293T cells and found that DUB3 increased BRD4 protein expression in a dose dependent manner.
Unexpectedly, knockdown of DUB3 not only decreased BRD4 protein levels in SPOP F133V expressing DU145 cells but also sensitized SPOP-F133V cells to JQ1 treatment, suggesting the presence of a SPOP ind[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Moreover, knockdown of DUB3 largely decreased BRD4 protein levels, but little or no further reduction in BRD4 protein expression by co-treatment with PD0332991 was observed.
We further demonstrated that downregulation of BRD4 proteins caused by DUB3 knockdown was reversed by treating cells with the proteasome inhibitor MG132.
To directly assess whether Dub3 promotes metastasis in vivo, we intravenously injected Dub3-knockdown MDA-MB231 cells into female SCID mice and subjected these mice to bioluminescent imaging (BLI).
Dub3 knockdown after DOX treatment significantly decreased lung metastasis and lung weight, but these parameters showed no difference in control mice with or without DOX treatment (middle and right panels, XREF_FIG).
USP17 Knockdown Impairs Tumor Proliferation and Metastasis Through Targeting MMPs Because degradation of the basement membrane by MMPs is required for tumor cell migration and invasion ( 16,17 ) , we sought to determine whether MMPs were responsible for USP17-dependent growth and invasion .
It has been reported that Snail1 pathway is involved in the progression of many diseases , for instance , Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation.25 CLDN6 promotes tumor progression through the YAP1-snail1 axis in gastric cancer.26 Moreover , it has been reported that Snail1 has involved the progression of DN.27 Consistent with our research , mRNA and protein expression of Snail1 was decreased in PVT1-KD MCs , which was reversed by treating with miR-325-3p inhibitor .
Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis.
Our results (shown in XREF_FIG and XREF_SUPPLEMENTARY) demonstrate DUB3 's ability to increase breast cancer cell migration and metastasis by targeting SNAIL1, thereby supporting our hypothesis that DUB3 promotes breast carcinoma metastasis in patients.
Based on these genomic data and our finding that NCOR2 represses DUB3 expression in cultured cells, we hypothesized that loss of NCOR due to deletions or mutations results in DUB3 upregulation, which [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
We found that knockdown of NCOR2 by two independent shRNAs increased expression of DUB3 and BRD4 proteins, but not BRD2 and BRD3 proteins, while NCOR2 knockdown increased mRNA expression of DUB3, but [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
The NCOR2 gene is frequently deleted in castration resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells.
Using a gain-of-function approach, we demonstrated that overexpression of BRD4 elevated NCOR2 expression but repressed DUB3 at both the mRNA and protein levels in C4-2 cells.
USP17 promotes proliferation and invasion through PI3K / AKT activation in NSCLC Consistent with the findings from the USP17-OE cells , knock-down ( KD ) of USP17 decreased the protein expression levels of p-AKT and p-PI3K in NSCLC cells ( NC vs. KD , P < 0.0001 ; Fig. 6A-F ) .
Suppression of Ubiquitin-Specific Peptidase 17 ( USP17 ) Inhibits Tumorigenesis and Invasion in Non-Small Cell Lung Cancer Cells USP17 PROMOTES TUMORIGENESIS AND METASTASIS IN NSCLC ZHANG , YUAN , AND ZHENG Recently , deubiquitinating enzymes ( DUBs ) are emerging as new regulators in cancer progression .
Taken together , our study showed that USP17 promotes tumorigenesis and invasion through regulation of MMPs ( MMP3 and MMP9 ) in NSCLC cells and provides a promising approach for NSCLC treatment and prevention .
Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis.
By blocking the interaction of Dub3 and Snail, WP1130 prevents the deubiquitination of Snail, thereby blocking cancer invasion, migration, and the establishment of CSC like properties.
Depletion of DUB3 significantly inhibited the migratory ability and invasiveness of MDA-MB-231 cells (XREF_FIG), although it did not affect cell proliferation (XREF_SUPPLEMENTARY).
Finally, we have demonstrated that constitutive expression of DUB-3 blocks proliferation and can initiate apoptosis in both IL-3-dependent Ba/F3 cells and NIH3T3 fibroblasts.
Consistently, Dub3 expression induced a morphologic change indicative of EMT (XREF_FIG), including downregulation of epithelial markers (E-cadherin, Claudin-7 and Occludin) and the upregulation of mesenchymal molecules (N-cadherin and Vimentin) (XREF_FIG, XREF_SUPPLEMENTARY).
Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis.
CDK4/6 mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a transcription factor that promotes epithelial-mesenchymal transition (EMT) and, therefore, invasiveness.
Besides, CDK4/6 mediated activation of DUB3 has been reported to be essential to deubiquitinate and stabilize SNAIL1, a key factor promoting EMT and involved in breast cancer metastasis 34.
These data suggest DUB3 is a critical upstream regulator of BRD4 protein stability and that inhibition of DUB3 by CDK4/6 inhibitor overcomes BET-inhibitor-induced elevation of BRD4 protein and BET inh[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Interestingly, Dub3 activity and expression, at both the mRNA and protein levels, can be induced by IL-6 through the JAK and STAT3 signaling pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].
In addition, the DUB-3 protein, induced by IL-4 and IL-6, is also involved in the regulation of cell growth and survival where its constitutive expression leads to growth suppression and apoptosis [25[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Curiously, the DUB3 gene, a part of the highly polymorphic RS447 megasatellite sequence, is induced by cytokines interleukin (IL-) 4 and IL-6 in certain mammalian cells XREF_BIBR XREF_BIBR.
ERRbeta knockdown in and DY131 stimulation of mouse ESCs reduces or enhances Dub3 and Cdc25A, respectively, and RNAi mediated inhibition of Dub3 or Cdc25A led these cells to differentiate.
To address the specific role of the two splice variants NCoA and SRC1A and NCoA and SRC1E on Esrrb mediated Dub3 transcription, we individually cotransfected each coactivators with Esrrb and measured the activity of a luciferase reporter gene.
Surprisingly, we also found an interaction through the Q rich domain, which seemed to convey inhibitory signals since deletion of this region resulted in increased Esrrb mediated Dub3 transcription (XREF_FIG).
As expected, only wild type Esrrb and not the C-terminally truncated receptor increased Dub3 transcriptional activity (XREF_FIG), indicating that coactivator recruitment through the C-terminus that contains the AF2 domain is essential to the Esrrb mediated transcriptional response on the Dub3 promoter.
These findings further highlight the complexity of the regulatory network of transcription factors in pluripotent mESCs and may explain why downregulation of Esrrb does not completely abolish Dub3 gene expression in mESCs XREF_BIBR.
Since Cdc25A degradation is beta-TrCP ubiquitin dependent [XREF_BIBR, XREF_BIBR], next, we checked whether CPX downregulates DUB3, a Cdc25A specific deubiquitinase, which protects Cdc25A from degradation by removing ubiquitin chain from Cdc25A [XREF_BIBR].
Individual cell tracking also revealed Dub3 knockdown reduced the velocity and directionality of cell migration, and strongly inhibited the net distance of cell migration in MDA-MB231 and MDA-MB157 cells (XREF_FIG, XREF_SUPPLEMENTARY).
Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis.
Moreover, these authors demonstrated that ectopic expression of DUB3 caused Nrf2 dependent chemotherapy resistance in colon cancer cell lines [XREF_BIBR].
Taken together , our study showed that USP17 promotes tumorigenesis and invasion through regulation of MMPs ( MMP3 and MMP9 ) in NSCLC cells and provides a promising approach for NSCLC treatment and prevention .
Suppression of Ubiquitin-Specific Peptidase 17 ( USP17 ) Inhibits Tumorigenesis and Invasion in Non-Small Cell Lung Cancer Cells USP17 PROMOTES TUMORIGENESIS AND METASTASIS IN NSCLC ZHANG , YUAN , AND ZHENG Recently , deubiquitinating enzymes ( DUBs ) are emerging as new regulators in cancer progression .
We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose dependent manner, whereas Dub3-knockdown decreased their protein levels.
When Dub3 was co-expressed with Slug in HEK293 cells, we found that Dub3 significantly increased protein levels of Slug, an effect comparable to treatment with proteasome inhibitor MG132 (top panel, Figure XREF_FIG).
To further define the mechanism of Dub3 mediated Slug and Twist stabilization, we performed co-immunoprecipitation (Co-IP) experiment using HEK293 cells expressing both Myc-Dub3 and Flag-Slug or HA-Twist.
By blocking the interaction of Dub3 and Snail, WP1130 prevents the deubiquitination of Snail, thereby blocking cancer invasion, migration, and the establishment of CSC like properties.
Using a gain-of-function approach, we demonstrated that overexpression of BRD4 elevated NCOR2 expression but repressed DUB3 at both the mRNA and protein levels in C4-2 cells.
Since we identified NCOR2 and HDAC10 as upstream repressors of DUB mRNA expression, we asked whether BRD4 modulates DUB3 expression by regulating NCOR2 and/or HDAC10.
Taken together, these data indicate that BRD4 induces downregulation of DUB3 through upregulation of NCOR2, which acts as a repressor of DUB3 transcription.
In addition, the DUB-3 protein, induced by IL-4 and IL-6, is also involved in the regulation of cell growth and survival where its constitutive expression leads to growth suppression and apoptosis [25[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
This transcriptional control appears to be very complex and gene specific and remains to be further clarified.We observed that while forced Dub3 expression could not inhibit differentiation upon LIF w[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose dependent manner, whereas Dub3-knockdown decreased their protein levels.
Thus DUB3 activity can promote the stability of LATS1/2 and AMOT, which act to reduce YAP activity and increase YAP turnover, while also increasing expression of ITCH, which can promote YAP turnover.
In support to this possibility, expression of the individual NCoA1 splice variants (NCoA and SRC1A or NCoA and SRC1E) in mESCs, both led to an increase of endogenous Dub3 mRNA without affecting Esrrb gene expression (XREF_SUPPLEMENTARY).
In contrast, NCoA2 and NCoA3 inversely correlated with Dub3 expression, suggesting that NCoA1 may contribute to the strong cell cycle dependent oscillation of Dub3 expression levels.
Since DUB3 deubiquitinates and stabilizes SNAIL1 and consequently decreases E-cadherin expression, we hypothesized that DUB3 is critical for breast cancer cell migration and invasion in vitro.
JQ1-induced upregulation of BRD4 protein was almost completely abolished by DUB3 knockdown or inhibition of DUB3 by the CDK4/6 inhibitor PD0332991 ( Figures 7 B and 7C).
We demonstrated that JQ1-induced upregulation of BRD4 protein was almost completely abolished by DUB3 knockdown or inhibition of DUB3 by CDK4/6 inhibitor PD0332991 ( xref ).
Hence , we hypothesized miR-542-5p might directly modulate AGO2 into RISC , subsequently the RISC leads to repression of DUB3 , resulting in the proliferation , migration , and cell cycle were all inhibited by pristimerin .
In light of this, we asked if AMOT and the related AMOTL1 and AMOTL2 proteins are required to mediate the effect of DUB3 on LATS kinase and YAP levels.
Similar to our observations, previous shRNA studies have also indicated that Dub3 knockdown reduces proliferation by inhibiting the G1-S phase cell cycle progression and inhibits chemotaxis [14,15,26][MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Instead, PD0332991 induces the inactivation of DUB3, destablization of SNAIL1 protein and decrease in cell migration, thereby reducing metastasis in xenograft models, both from a breast cancer patient and a TNBC cell line.
Only a small number of DUBs strongly affected both 53BP1 and RAD51 recruitment simultaneously, including USP29, an enzyme linked to H2A de-ubiquitylation and the recently reported HR modulator DUB3.
VSMCs isolated from 10 patients were subjected to in vitro WNT5A treatment with or without peg-SOD , and quantitative real time polymerase chain reaction ( q-RT-PCR ) confirmed that WNT5A increases the expression of USP17 ( Figure 8C ) .
We show that key USP17 substrates populate two pathways that drive cell cycle progression and that USP17 activity serves to promote one pathway but inhibit the other .
Only a small number of DUBs strongly affected both 53BP1 and RAD51 recruitment simultaneously, including USP29, an enzyme linked to H2A de-ubiquitylation and the recently reported HR modulator DUB3.
Overall , the findings of the present study demonstrate the promotion of NSCLC cell proliferation and viability by USP17 , via the activation of the PI3K / AKT pathway .
Our results showed that DUB3 inhibits YAP and TAZ activity; we asked whether this inhibition would affect Hippo mediated cell growth and proliferation.
Our data clearly indicated that the co-expression of DUB3 significantly reversed the inhibitory effect of RNF152 on RagA activation, confirming that RNF152 inhibits RagA activation by targeting RagA f[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
More recently, we have also reported that constitutive expression of DUB-3 can block cell proliferation [XREF_BIBR, XREF_BIBR] and subsequently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the ' CAAX ' box protease Ras converting enzyme 1 (RCE1) [XREF_BIBR].
More recently, we have also reported that constitutive expression of DUB-3 can block cell proliferation [XREF_BIBR, XREF_BIBR] and subsequently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the ' CAAX ' box protease Ras converting enzyme 1 (RCE1) [XREF_BIBR].
While Dub3 and mir21 are significantly modulated (with upregulation and downmodulation respectively) in PTEN active cell lines, their transcripts variation is far less evident than in PTEN inactive ones.
USP17 Knockdown Impairs Tumor Proliferation and Metastasis Through Targeting MMPs Because degradation of the basement membrane by MMPs is required for tumor cell migration and invasion ( 16,17 ) , we sought to determine whether MMPs were responsible for USP17-dependent growth and invasion .
Interestingly , our Western blot analysis found that depletion of USP17 dramatically reduced MMP3 and MMP9 but not MMP2 expression in both NSCLC cells ( Fig. 4A and B ) .
Interestingly , our Western blot analysis found that depletion of USP17 dramatically reduced MMP3 and MMP9 but not MMP2 expression in both NSCLC cells ( Fig. 4A and B ) .
Interestingly , our Western blot analysis found that depletion of USP17 dramatically reduced MMP3 and MMP9 but not MMP2 expression in both NSCLC cells ( Fig. 4A and B ) .
Conversely, depletion of DUB3 or USP7 reduces Geminin levels, and DUB3 knockdown increases re-replication events, analogous to the effect of Geminin depletion.
In contrast, acute Dub3 overexpression produced a signature response to oncogene induction : cells accumulated in S and G2 because of replication stress, and activated a DNA damage response.
Accordingly, overexpression of DUB3 increased the level of ectopically expressed full-length BRD4 protein in a dose dependent manner but had no effect on BRD4DeltaCTM mutant, BRD2 or BRD3 in PC-3 cell[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Accordingly, overexpression of DUB3 increased the level of ectopically expressed full-length BRD4 protein in a dose dependent manner but had no effect on BRD4DeltaCTM mutant, BRD2 or BRD3 in PC-3 cell[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Given that JQ1 induces upregulation of DUB3 at both the mRNA and protein levels in different cell types (Borbely et al., 2015) and DUB3 binds to BRD4 and promotes its deubiquitination and protein stab[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
Depletion of ITCH from this complex reduces the effects of DUB3 on YAP, and this effect was stronger when NEDD4, another E3 ligase was also removed (XREF_FIG).
To determine which member in the class I/II HDAC subfamilies mediates the transcriptional repression of DUB3 expression, we performed an unbiased screen by knocking down all 11 class I/II HDACs indivi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
We also failed to detect any physical interaction between BRE and DUB3 or beta-TRCP, indicating that BRE overexpression mediated CDC25A deregulation is independent of beta-TRCP and DUB3.
In light of this, we asked if AMOT and the related AMOTL1 and AMOTL2 proteins are required to mediate the effect of DUB3 on LATS kinase and YAP levels.
In light of this, we asked if AMOT and the related AMOTL1 and AMOTL2 proteins are required to mediate the effect of DUB3 on LATS kinase and YAP levels.