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

Yuki Ishii,Krishna K Kolluri,Adam Pennycuick,Xidan Zhang,Ersilia Nigro,Doraid Alrifai,Elaine Borg,Mary Falzon,Khalid Shah,Neelam Kumar,Sam M Janes

doi:10.1016/j.jbc.2021.101223

Yuki Ishii, Krishna K Kolluri + Show 9 more

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https://doi.org/10.1016/j.jbc.2021.101223

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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 DR4 and DR5, 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 DR4 and DR5. Knockdown of YY1 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.

Highlights

Malignant pleural mesothelioma (MPM) tumor biology have led to the development of multiple novel targeted agents currently in preclinical and clinical development
We have previously demonstrated that loss of BRCA1associated protein 1 (BAP1) function results in sensitivity to the death receptor (DR) agonist recombinant tumor necrosis factor (TNF)–related apoptosis– inducing ligand [23]
We have previously shown that MPM cells with loss of BAP1 function are more sensitive to treatment with rTRAIL [23]

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MPM tumor biology have led to the development of multiple novel targeted agents currently in preclinical and clinical development. The response to drugs that act upon these pathways, including poly(ADPribose) polymerase (PARP) and enhancer of zeste homolog 2 inhibitors, has been shown to be increased in the absence of BAP1 function [20] Clinical trials of these drugs in BAP1mutant MPM are underway [21]. TRAIL is a member of the TNF cytokine superfamily It activates the extrinsic apoptotic pathway by binding to either of two DRs, DR4 or DR5, which leads to the recruitment of the adaptor protein Fas-associated protein with death domain and caspase-8 to form the deathinducing signaling complex [24]. We hypothesize that BAP1 activity modulates expression of proteins of the extrinsic and intrinsic apoptosis pathways with an increase in proapoptotic protein expression in the absence of BAP1 activity We demonstrate that both BAP1 activity and rTRAIL sensitivity correlate with expression of the DRs, DR4 and DR5, at the transcriptional level. As BAP1 lacks DNA-binding sites, we searched for the transcriptional factor that cooperates with BAP1 to modulate expression of DR4 and DR5 identifying the polycomb group protein Ying Yang 1 (YY1)

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