Loss of BAP1 Results in Growth Inhibition and Enhances Mesenchymal–Epithelial Transition in Kidney Tumor Cells

BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C-terminal hydrolase family of deubiquitinating enzymes and is implicated in transcriptional regulation. The BAP1 gene is mutated in about 10% of patients with ccRCC, the most common form of renal cancer, suggesting that BAP1 is a tumor suppressor. However, whether BAP1 influences the progression of ccRCC tumors expressing wild-type (WT) BAP1 is unclear. Here, we assessed the expression and function of BAP1 using human ccRCC specimens and cell lines. Analysis of datasets in The Cancer Genome Atlas revealed that lower BAP1 expression is correlated with longer overall survival of ccRCC patients. We established human ccRCC cell lines with stable BAP1 knockout and performed multiomic analysis of BAP1-mediated cellular processes. BAP1 knockout downregulated proteins associated with protein synthesis, resulting in decreased cell growth. Importantly, loss of BAP1 decreased the formation of stress fibers and membrane protrusions and induced migration and invasion defects. BAP1 knockout in ccRCC cells also downregulated the expression of transcriptional repressor protein Snail and decreased the activity of Rho family GTPases, promoting the cells to undergo mesenchymal-epithelial transition. Unexpectedly, quantitative proteomics also showed that BAP1 knockout increased expression of several amino acid transporters and multiple tyrosine kinases, including the epidermal growth factor receptor. Overall, our results suggest that BAP1 regulates multiple cellular processes, and we also uncover a new role for BAP1 in controlling mesenchymal-epithelial transition in ccRCC cells. BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C-terminal hydrolase family of deubiquitinating enzymes and is implicated in transcriptional regulation. The BAP1 gene is mutated in about 10% of patients with ccRCC, the most common form of renal cancer, suggesting that BAP1 is a tumor suppressor. However, whether BAP1 influences the progression of ccRCC tumors expressing wild-type (WT) BAP1 is unclear. Here, we assessed the expression and function of BAP1 using human ccRCC specimens and cell lines. Analysis of datasets in The Cancer Genome Atlas revealed that lower BAP1 expression is correlated with longer overall survival of ccRCC patients. We established human ccRCC cell lines with stable BAP1 knockout and performed multiomic analysis of BAP1-mediated cellular processes. BAP1 knockout downregulated proteins associated with protein synthesis, resulting in decreased cell growth. Importantly, loss of BAP1 decreased the formation of stress fibers and membrane protrusions and induced migration and invasion defects. BAP1 knockout in ccRCC cells also downregulated the expression of transcriptional repressor protein Snail and decreased the activity of Rho family GTPases, promoting the cells to undergo mesenchymal-epithelial transition. Unexpectedly, quantitative proteomics also showed that BAP1 knockout increased expression of several amino acid transporters and multiple tyrosine kinases, including the epidermal growth factor receptor. Overall, our results suggest that BAP1 regulates multiple cellular processes, and we also uncover a new role for BAP1 in controlling mesenchymal-epithelial transition in ccRCC cells. BAP1 1The abbreviations used are:BAP1BRCA1-associated protein 1ccRCCclear cell renal cell carcinomaBRCA1breast cancer type 1 susceptibility proteinIP3R3inositol 1,4,5-trisphosphate receptor type 3SETD2histone-lysine N-methyltransferase SETD2KDM5Clysine-specific demethylase 5CEMTepithelial–mesenchymal transition. 1The abbreviations used are:BAP1BRCA1-associated protein 1ccRCCclear cell renal cell carcinomaBRCA1breast cancer type 1 susceptibility proteinIP3R3inositol 1,4,5-trisphosphate receptor type 3SETD2histone-lysine N-methyltransferase SETD2KDM5Clysine-specific demethylase 5CEMTepithelial–mesenchymal transition. is a member of the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes (DUBs) (1Jensen D.E. Proctor M. Marquis S.T. Gardner H.P. Ha S.I. Chodosh L.A. Ishov A.M. Tommerup N. Vissing H. Sekido Y. Minna J. Borodovsky A. Schultz D.C. Wilkinson K.D. Maul G.G. Barlev N. Berger S.L. Prendergast G.C. Rauscher 3rd., F.J. BAP1: A novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.Oncogene. 1998; 16: 1097-1112Crossref PubMed Scopus (586) Google Scholar). Histone H2A (Lys119) was the first identified substrate of BAP1 (2Scheuermann J.C. de Ayala Alonso A.G. Oktaba K. Ly-Hartig N. McGinty R.K. Fraterman S. Wilm M. Muir T.W. Müller J. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.Nature. 2010; 465: 243-247Crossref PubMed Scopus (565) Google Scholar); since then, many other targets have been reported, including the transcription factor Krueppel-like factor 5, the cytoskeletal protein γ-tubulin, and the receptor protein IP3R3 (3Qin J. Zhou Z. Chen W. Wang C. Zhang H. Ge G. Shao M. You D. Fan Z. Xia H. Liu R. Chen C. BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5.Nat. Commun. 2015; 6: 8471Crossref PubMed Scopus (125) Google Scholar, 4Bononi A. Giorgi C. Patergnani S. Larson D. Verbruggen K. Tanji M. Pellegrini L. Signorato V. Olivetto F. Pastorino S. Nasu M. Napolitano A. Gaudino G. Morris P. Sakamoto G. Ferris L.K. Danese A. Raimondi A. Tacchetti C. Kuchay S. Pass H.I. Affar E.B. Yang H. Pinton P. Carbone M. BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation.Nature. 2017; 546: 549-553Crossref PubMed Scopus (242) Google Scholar, 5Zarrizi R. Menard J.A. Belting M. Massoumi R. Deubiquitination of gamma-tubulin by BAP1 prevents chromosome instability in breast cancer cells.Cancer Res. 2014; 74: 6499-6508Crossref PubMed Scopus (57) Google Scholar). Calypso, the Drosophila orthologue of BAP1, interacts with the additional sex combs protein to form the polycomb-repressive deubiquitinase complex, which is involved in repression of HOX genes during embryo development (2Scheuermann J.C. de Ayala Alonso A.G. Oktaba K. Ly-Hartig N. McGinty R.K. Fraterman S. Wilm M. Muir T.W. Müller J. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.Nature. 2010; 465: 243-247Crossref PubMed Scopus (565) Google Scholar). BAP1 has been shown to interact with several transcription factors and epigenetic modifiers (6Carbone M. Yang H. Pass H.I. Krausz T. Testa J.R. Gaudino G. BAP1 and cancer.Nat. Rev. Cancer. 2013; 13: 153-159Crossref PubMed Scopus (438) Google Scholar), indicating that it plays important roles in transcriptional regulation. Consistent with this, BAP1 is known to be involved in a variety of cellular processes, such as cell cycle progression, endoplasmic reticulum stress response, and DNA repair (7Eletr Z.M. Wilkinson K.D. An emerging model for BAP1's role in regulating cell cycle progression.Cell Biochem. Biophys. 2011; 60: 3-11Crossref PubMed Scopus (95) Google Scholar, 8Ismail I.H. Davidson R. Gagné J.P. Xu Z.Z. Poirier G.G. Hendzel M.J. Germline mutations in BAP1 impair its function in DNA double-strand break repair.Cancer Res. 2014; 74: 4282-4294Crossref PubMed Scopus (141) Google Scholar, 9Yu H. Pak H. Hammond-Martel I. Ghram M. Rodrigue A. Daou S. Barbour H. Corbeil L. Hebert J. Drobetsky E. Masson J.Y. Di Noia J.M. Affar el.B. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair.Proc. Natl. Acad. Sci. U.S.A. 2014; 111: 285-290Crossref PubMed Scopus (244) Google Scholar, 10Dai F. Lee H. Zhang Y. Zhuang L. Yao H. Xi Y. Xiao Z.D. You M.J. Li W. Su X. Gan B. BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.Proc. Natl. Acad. Sci. U.S.A. 2017; 114: 3192-3197Crossref PubMed Scopus (61) Google Scholar). BRCA1-associated protein 1 clear cell renal cell carcinoma breast cancer type 1 susceptibility protein inositol 1,4,5-trisphosphate receptor type 3 histone-lysine N-methyltransferase SETD2 lysine-specific demethylase 5C epithelial–mesenchymal transition. BRCA1-associated protein 1 clear cell renal cell carcinoma breast cancer type 1 susceptibility protein inositol 1,4,5-trisphosphate receptor type 3 histone-lysine N-methyltransferase SETD2 lysine-specific demethylase 5C epithelial–mesenchymal transition. BAP1 was originally identified as a ubiquitin C-terminal hydrolase that binds to the RING finger domain of BRCA1 and enhances BRCA1-mediated tumor suppressive activity (1Jensen D.E. Proctor M. Marquis S.T. Gardner H.P. Ha S.I. Chodosh L.A. Ishov A.M. Tommerup N. Vissing H. Sekido Y. Minna J. Borodovsky A. Schultz D.C. Wilkinson K.D. Maul G.G. Barlev N. Berger S.L. Prendergast G.C. Rauscher 3rd., F.J. BAP1: A novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.Oncogene. 1998; 16: 1097-1112Crossref PubMed Scopus (586) Google Scholar). However, BAP1 also exhibits tumor suppressive behavior in a BRCA1-independent manner (11Ventii K.H. Devi N.S. Friedrich K.L. Chernova T.A. Tighiouart M. Van Meir E.G. Wilkinson K.D. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.Cancer Res. 2008; 68: 6953-6962Crossref PubMed Scopus (257) Google Scholar, 12Yu M. Liang H. Fu Z. Wang X. Liao Z. Zhou Y. Liu Y. Wang Y. Hong Y. Zhou X. Yan X. Yu M. Ma M. Zhang W. Guo B. Zhang J. Zen K. Zhang C.Y. Wang T. Zhang Q. Chen X. BAP1 suppresses lung cancer progression and is inhibited by miR-31.Oncotarget. 2016; 7: 13742-13753Crossref PubMed Scopus (34) Google Scholar). BAP1 is located on chromosome 3p21 in a region frequently altered in various cancers, such as mesothelioma and uveal melanoma (13Harbour J.W. Onken M.D. Roberson E.D. Duan S. Cao L. L.A. C. A.M. of BAP1 in uveal 2010; PubMed Scopus Google Scholar, M. M. S. T. Wang L. J. B. C. R. S. Zhou Q. R. A. V. M. The nuclear deubiquitinase BAP1 is by mutations and in 2011; PubMed Scopus Google Scholar), suggesting that BAP1 is a tumor suppressor. of have that of BAP1 inhibits the proliferation of various cell (3Qin J. Zhou Z. Chen W. Wang C. Zhang H. Ge G. Shao M. You D. Fan Z. Xia H. Liu R. Chen C. BAP1 promotes breast cancer cell proliferation and metastasis by deubiquitinating KLF5.Nat. Commun. 2015; 6: 8471Crossref PubMed Scopus (125) Google Scholar, 9Yu H. Pak H. Hammond-Martel I. Ghram M. Rodrigue A. Daou S. Barbour H. Corbeil L. Hebert J. Drobetsky E. Masson J.Y. Di Noia J.M. Affar el.B. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair.Proc. Natl. Acad. Sci. U.S.A. 2014; 111: 285-290Crossref PubMed Scopus (244) Google Scholar, Y. J.A. A. The deubiquitinating BAP1 regulates cell growth with PubMed Scopus Google Scholar, S. S. A. D. M. Lee J. Liu J. K. of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle cell factor PubMed Scopus Google Scholar, H. W. A. R. H. M. T. BRCA1-associated protein 1 with RING Res. PubMed Scopus Google Scholar), and expression of BAP1 with survival of patients with mesothelioma L. F. I. T. BAP1 protein is a progression factor in Res. 2014; PubMed Scopus Google Scholar, F. E. Napolitano A. S. E. Pass H. Yang H. Carbone M. patients with BAP1 mutations have 2015; PubMed Scopus Google Scholar). results suggest that BAP1 plays roles in cancer cell carcinoma is the and most common cancer in and the various clear cell is the most common and for of B. A. V. A. G. A. of renal cell 2015; PubMed Scopus Google Scholar, B. cell PubMed Scopus Google Scholar). have revealed that BAP1 is mutated in about 10% of and BAP1 is associated with overall survival in patients with S. S. Liao A. N. A. Wang S. T. L. S. P. L. T. S. Y. V. W. N. M. P. J. BAP1 loss a new of renal cell PubMed Scopus Google Scholar, B. S. A. M. M. Lee W. Chen Lee and with in patients with clear cell renal cell Cancer. 2017; PubMed Scopus Google Scholar). BAP1 is also associated with of the of in ccRCC S. S. Liao A. N. A. Wang S. T. L. S. P. L. T. S. Y. V. W. N. M. P. J. BAP1 loss a new of renal cell PubMed Scopus Google and has been to be for to also for to F. M. S. M. G. F. L. A. M. G. S. R. BAP1, and SETD2 in renal cell and targets for Rev. 2015; PubMed Scopus Google Scholar). the of ccRCC M. S. J. I. R. N. N. P. B. S. A. B. S. G. L. M. S. A. C. and of clear cell renal cell by 2014; PubMed Scopus Google Scholar, E. K. F. Z. H. A. in 2011; 60: PubMed Scopus Google Scholar), it is important to BAP1 function in the of ccRCC patients to and targets for the function of BAP1 in ccRCC, we used to BAP1 in human ccRCC cell lines and performed and We that BAP1 knockout genes involved in cell cytoskeletal and cell that BAP1 inhibited the altered the and the migration and invasion of ccRCC cells. results a of BAP1-mediated cellular in ccRCC and that it plays roles in cytoskeletal and cell lines the cell of of and cells in with 10% and in a with Genome for of BAP1 was performed as J. V. Zhang F. Genome using the 2013; PubMed Scopus Google with that used to J. Wang J. B. Chen L. Su Y. Yang J. Zhang W. X. X. J. 2014; PubMed Scopus Google by the to the and and cells with cells cells and with cells by in a to and by was performed on BAP1 knockout and cells used as and cell the was used to quantitative quantitative for the and of and on the that the of the proteins the was to that the is the for The used to the of identified and was used to the of the proteins by analysis using of protein in used to was to the of protein with with of protein with for and with for in the with The with and with The of and by and by was by in a with which was to a The was to in the The was to with a of and the cycle was 3 the most with and by of for stable with amino in cell with of and the was The with a of of and of The the human on using the of The as was was on and on as the on and on protein as the and the was to using the by a The was to and was used to the of identified and BAP1 cells in and and cells with and protein The was performed using the the was with for and with acid for in the with The with and The in and with for the by for and for and by The was by for The and the as with and as and on was as and expression using the of and was with and the of was by have the that be used for was used the was by a and by was used for The of and as A. Google Scholar). and with with for of of cell type with and for the by and with of for The proteins to with with and for the was The protein was by of proteins was by and a with for 1 the membrane was with with with for 1 The membrane was by with BAP1 was H2A Snail and form was by and to by to was performed by with was used as expression was by used for in and in in with a the cells several with and by The of the with for 3 cells and in the with and the lower with 10% the of the and the cells on the lower with and with The of cells with and on the lower of was performed the J. Scholar). and BAP1 cells and with for and and the with of with and with protein A and DNA by used for in on a cell cells in with for with for in and with in for in and with The with by and by The Snail was and cells in was with and activity was by using the the The in with to and in cells proliferation was by to the was with a with for and analysis with as was used to the and lower to be A survival was by and the J. survival to and Sci. 2016; Scopus Google and in the of the and lower whether expression of BAP1 with the survival of ccRCC we datasets Genome Atlas of clear cell renal cell 2013; PubMed Scopus Google in The Cancer Genome of and of of the patients BAP1 the analysis we that lower BAP1 expression correlated with longer overall survival patients BAP1 that BAP1 complex roles in tumor progression other a tumor suppressor. the function of BAP1 in ccRCC progression, we used with to BAP1 in the human and ccRCC cell lines with The region of BAP1 amino and acid in which is the (1Jensen D.E. Proctor M. Marquis S.T. Gardner H.P. Ha S.I. Chodosh L.A. Ishov A.M. Tommerup N. Vissing H. Sekido Y. Minna J. Borodovsky A. Schultz D.C. Wilkinson K.D. Maul G.G. Barlev N. Berger S.L. Prendergast G.C. Rauscher 3rd., F.J. BAP1: A novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.Oncogene. 1998; 16: 1097-1112Crossref PubMed Scopus (586) Google Scholar). we to domain and to the BAP1 was by shown in about was in of BAP1 to stable cell BAP1 was also by analysis H2A is a substrate of BAP1 (2Scheuermann J.C. de Ayala Alonso A.G. Oktaba K. Ly-Hartig N. McGinty R.K. Fraterman S. Wilm M. Muir T.W. Müller J. Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.Nature. 2010; 465: 243-247Crossref PubMed Scopus (565) Google Scholar). analysis showed that H2A was increased in BAP1 cells with the cells indicating that BAP1 regulates gene expression in cells. BAP1 is a deubiquitinating we in the of BAP1 cells with cells. analysis of proteins with increased in cells showed that BAP1 in and in cells we performed quantitative analysis to the of BAP1 on in ccRCC cells. we identified of which as proteins to the of protein of the and of showed of A in The for downregulated proteins was using a and in for and Res. 6: PubMed Scopus Google Scholar). to our we about to of on this, the was the in the and in the proteins with and analysis was performed to the of the The most for the and and proteins and proteins in which that BAP1 was involved in and cell we the to analysis and that proteins to cell and in and cell proliferation in and by cellular and and cellular and cell proliferation was by cell and cellular growth and and cell to cell and and to cell the proteins downregulated by BAP1 which which for cell and a protein that plays a role in to cell and also in the results analysis of results that BAP1 a role in of cell and cytoskeletal We the of BAP1 on cell migration in using a migration of BAP1 cells the of the migration of BAP1 cells was results with the ccRCC cell we the of BAP1 on behavior using a with the of BAP1 cells was lower that of the cells and results that BAP1 plays important role in the and behavior of ccRCC cells. The in ccRCC cell that BAP1 be involved in the the which for development also for the progression of tumors J.P. H. in development and PubMed Scopus Google Scholar, X. A of cancer 2015; PubMed Scopus Google Scholar). the promotes tumor invasion and cells undergo to form new which for of cancer in D. The of PubMed Scopus Google Scholar, D. of The 2011; PubMed Scopus Google Scholar). The transcription factor Snail plays a role in by regulating the expression of several and such as and A. I. A. M.J. F. The transcription factor Snail by PubMed Scopus Google Scholar). Consistent with the results of the migration and invasion analysis of ccRCC cells showed a in the expression of and in BAP1 cells with cells which a role for BAP1 in the also showed that proteins associated with protein and growth factor downregulated in BAP1 cells BAP1 H2A on which is epigenetic implicated in transcription repression W. P. Wang J. G. J. Histone H2A transcription by transcriptional 2008; PubMed Scopus Google Scholar, R. S. H.I. Müller M. Müller J. Histone H2A promotes in Polycomb 2014; PubMed Scopus Google Scholar), we that BAP1 Snail expression the transcription this, was performed and the that Snail was downregulated in BAP1 cells analysis showed that (Lys119) was in the Snail gene region we performed in which expression was by Snail activity was in cells with the expression with the which that BAP1 results that BAP1 regulates Snail by deubiquitinating H2A in the Snail gene region and that loss of BAP1 in cells induced by Snail the by which BAP1 regulates the migration and invasion of ccRCC we cytoskeletal in BAP1 and cells using the protein shown in cells with BAP1 decreased formation of stress and and The Rho family and of cytoskeletal and roles in cell and Rho in the formation of stress fibers and modulates cell and regulates and and is involved in formation and K. S. M. of the and cell by the Rho family in Rev. Biochem. 68: PubMed Scopus Google Scholar). cell the of cell and membrane protrusions the and Rho promotes for M. A. Rho the PubMed Scopus Google Scholar). Consistent with and the of BAP1 on ccRCC cell and activity showed that and downregulated in BAP1 cells with cells and quantitative analysis showed that protein and of Rho family member indicating that BAP1 regulates expression the have that Snail regulates cell the expression and activity of Rho family V. B. D. Morris M. Snail promotes cell migration as as during cancer progression.Cell 2015; PubMed Scopus Google Scholar, S. and Rho regulates and of cancer cells by and PubMed Scopus Google Scholar, C. G. I. R. K. G. M. C. Snail the migration of tumor 2016; PubMed Scopus Google Scholar, A. Wang Q. Z. W. Xi L. Q. Wang S. Zhou J. Xu G. L. Chen G. Ma D. expression of Snail breast cancer cell by the expression and the activity of 2013; 6: PubMed Scopus Google Scholar). loss of BAP1 downregulated the expression of and in the decreased expression and activity of Rho family GTPases, Importantly, the in stress and formation and induced by loss of BAP1 was in and cell lines. a of the proteins in BAP1 cells involved in cellular to cell proliferation we cell proliferation using the loss of BAP1 decreased the growth of and and cells. analysis revealed a of in BAP1 cells it that the growth of cells was to decreased protein whether BAP1 cell cycle progression, we performed analysis of ccRCC cells with the cycle analysis showed that BAP1 in cells induced with that BAP1 progression in cells H. W. A. R. H. M. T. BRCA1-associated protein 1 with RING Res. PubMed Scopus Google Scholar). we also that BAP1 several transporters and growth in ccRCC cells. transporters of amino and and epidermal growth factor growth factor and growth factor receptor that BAP1 plays complex roles in cell growth regulation. have shown that epigenetic modifiers such as protein BAP1, and frequently mutated in and other tumors (13Harbour J.W. Onken M.D. Roberson E.D. Duan S. Cao L. L.A. C. A.M. of BAP1 in uveal 2010; PubMed Scopus Google Scholar, M. S. J. I. R. N. N. P. B. S. A. B. S. G. L. M. S. A. C. and of clear cell renal cell by 2014; PubMed Scopus Google Scholar, in renal cell Rev. PubMed Scopus Google Scholar, and metabolic of clear cell renal cell Biophys. PubMed Scopus Google Scholar, the for cancer SETD2 and the of 2017; 7: PubMed Scopus Google Scholar). proteins involved in regulating cellular processes, including DNA cytoskeletal and transcription in renal cell Rev. PubMed Scopus Google Scholar). have that BAP1 as a tumor suppressor (1Jensen D.E. Proctor M. Marquis S.T. Gardner H.P. Ha S.I. Chodosh L.A. Ishov A.M. Tommerup N. Vissing H. Sekido Y. Minna J. Borodovsky A. Schultz D.C. Wilkinson K.D. Maul G.G. Barlev N. Berger S.L. Prendergast G.C. Rauscher 3rd., F.J. BAP1: A novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression.Oncogene. 1998; 16: 1097-1112Crossref PubMed Scopus (586) Google Scholar, K.H. Devi N.S. Friedrich K.L. Chernova T.A. Tighiouart M. Van Meir E.G. Wilkinson K.D. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.Cancer Res. 2008; 68: 6953-6962Crossref PubMed Scopus (257) Google Scholar), that it also plays a role in promoting cell proliferation H. Pak H. Hammond-Martel I. Ghram M. Rodrigue A. Daou S. Barbour H. Corbeil L. Hebert J. Drobetsky E. Masson J.Y. Di Noia J.M. Affar el.B. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair.Proc. Natl. Acad. Sci. U.S.A. 2014; 111: 285-290Crossref PubMed Scopus (244) Google Scholar, 10Dai F. Lee H. Zhang Y. Zhuang L. Yao H. Xi Y. Xiao Z.D. You M.J. Li W. Su X. Gan B. BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.Proc. Natl. Acad. Sci. U.S.A. 2017; 114: 3192-3197Crossref PubMed Scopus (61) Google Scholar, Y. J.A. A. The deubiquitinating BAP1 regulates cell growth with PubMed Scopus Google Scholar). BAP1 is to be mutated in about 10% of ccRCC the we that lower expression of BAP1 in ccRCC correlated with longer overall suggesting that BAP1 complex roles in ccRCC other a tumor suppressor. analysis showed that BAP1 was associated with of gene quantitative analysis revealed that BAP1 altered in ccRCC the expression of proteins associated with cell cytoskeletal and cell by of ccRCC cell and The and downregulated in BAP1 and we that BAP1 regulates Snail transcription by deubiquitinating H2A in the Snail gene Consistent with the of and decreased by BAP1 resulting in a loss of stress and The of cell growth in BAP1 ccRCC cells be to a in protein has identified a of the complex as a gene H. N. Daou S. Hammond-Martel I. J. G. Rauscher F.J. Drobetsky E. E. Y. Affar B. The ubiquitin hydrolase BAP1 a complex with and and is a of gene 2010; PubMed Scopus Google Scholar). Consistent with this, we that BAP1 in ccRCC cells expression by with BAP1 cells protein and of the protein 1 also downregulated in BAP1 cells have shown that is in of ccRCC tumors A. J.C. M. J. G. K. F. B. P. A. P. R. F. N. and in clear cell renal cell carcinoma of patients with 2015; Google Scholar, L. A. J. A. J. B. B. R. G. A. J. M. Y. S. S. K. N. of expression with clear cell renal cell with J. Cancer. 2017; PubMed Scopus Google and that is to cell of L. S. L.A. Zhang X. X. D. W. L. Wang J. J. M. C. D. S. M. G. S. M. J.W. B. Chen L. D. Wang S. J.M. is of cell expression and Commun. 2014; PubMed Scopus Google Scholar). the results to a role for BAP1 in we have that of BAP1 in ccRCC cells altered cellular cell and induced a Importantly, Snail and Rho family roles in the by results also that BAP1 roles in tumor The have been to the the with the We the the for Analysis of for We Xia for the with gene We M. for the of a of with