BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma

• DOI: 10.1016/j.jbc.2021.101223
• Publication Date: 2021-09-29T04:33:58Z
• Authors: Yuki Ishii; Krishna K. Kolluri; Adam Pennycuick; Xidan Zhang; Ersilia Nigro; Doraid Alrifai; Elaine Borg; Mary Falzon; Khalid Shah; Neelam Kumar; Sam M. Janes
• Keywords: BAP1

Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of pleura, with few available treatment options. We recently reported that loss function nuclear deubiquitinase BRCA1-associated protein 1 (BAP1), frequent event in MPM, associated sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. As potential underlying mechanism, here we report BAP1 negatively regulates expression TRAIL receptors: death receptor 4 (DR4) 5 (DR5). Using tissue microarrays samples MPM patients, found strong inverse correlation between expression. knockdown increased DR4 DR5 expression, whereas overexpression had opposite effect. Reporter assays confirmed wt-BAP1, but not catalytically inactive mutant, reduced promoter activities DR5, suggesting activity required for regulation gene Co-immunoprecipitation studies demonstrated direct binding transcription factor Ying Yang (YY1), chromatin immunoprecipitation revealed YY1 be enriched regions DR5. Knockdown also TRAIL. These results suggest cooperatively repress receptors. Our finding directly extrinsic apoptotic pathway will provide new insights into role development other cancers mutations.