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• W3204927497 endingPage "101223" @default.
• W3204927497 startingPage "101223" @default.
• W3204927497 abstract "Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the pleura, with few available treatment options. We recently reported that loss of function of the nuclear deubiquitinase BRCA1-associated protein 1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated apoptosis. As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptor 4 (DR4) and death receptor 5 (DR5). Using tissue microarrays of tumor samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptor expression. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wt-BAP1, but not catalytically inactive BAP1 mutant, reduced promoter activities of <i>DR4</i> and <i>DR5</i>, suggesting deubiquitinase activity is required for the regulation of gene expression. Co-immunoprecipitation studies demonstrated direct binding of BAP1 to the transcription factor Ying Yang 1 (YY1), and chromatin immunoprecipitation assays revealed BAP1 and YY1 to be enriched in the promoter regions of <i>DR4</i> and <i>DR5</i>. Knockdown of <i>YY1</i> also increased DR4 and DR5 expression and sensitivity to TRAIL. These results suggest that BAP1 and YY1 cooperatively repress transcription of TRAIL receptors. Our finding that BAP1 directly regulates the extrinsic apoptotic pathway will provide new insights into the role of BAP1 in the development of MPM and other cancers with frequent BAP1 mutations." @default.
• W3204927497 created "2021-10-11" @default.
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• W3204927497 date "2021-11-01" @default.
• W3204927497 modified "2023-09-30" @default.
• W3204927497 title "BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma" @default.
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• W3204927497 doi "https://doi.org/10.1016/j.jbc.2021.101223" @default.
• W3204927497 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8545693" @default.
• W3204927497 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34597666" @default.
• W3204927497 hasPublicationYear "2021" @default.
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