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

Our plain-English summary of BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma, by Y. Ishii, K.K. Kolluri, A. Pennycuick, et al (The Journal of Biological Chemistry, 2021).

The study

• Authors: Y. Ishii, K.K. Kolluri, A. Pennycuick, X. Zhang, E. Nigro, D. Alrifai, E. Borg, M. Falzon, K. Shah, N. Kumar, S.M. Janes
• Journal: The Journal of Biological Chemistry
• Published: 2021;297(5):101223
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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 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.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

In plain English

This was a laboratory study of malignant pleural mesothelioma. It looked at a gene called BAP1, which is often altered in this cancer, and two cell-surface 'death receptors', DR4 and DR5, that respond to a molecule called TRAIL, which can trigger cancer cells to die. The study did not examine asbestos exposure. In tumor tissue (88 cores from 32 patients), samples lacking BAP1 in the cell nucleus showed higher DR4 and DR5 staining (p = 0.024 for DR4, p = 0.0092 for DR5). BAP1-mutant mesothelioma cell lines also had higher levels than cell lines with normal BAP1. Reducing BAP1 raised DR4 and DR5 in mesothelioma and kidney cancer cells, but not in normal lung fibroblasts or airway lining cells. BAP1 bound a partner protein, YY1, and both were found at the DR4 and DR5 gene control regions. Reducing YY1 increased TRAIL sensitivity in cells with normal BAP1, but not in BAP1-mutant cells. The authors concluded that BAP1 and YY1 together repress DR4 and DR5, which requires BAP1's enzyme activity. They noted that receptor levels alone could not explain TRAIL sensitivity in some cell lines.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using human mesothelioma tumor tissue microarrays, mesothelioma and kidney cancer cell lines, and early passage mesothelioma cells
• Who was studied: Tumor tissue microarray cores from patients with malignant pleural mesothelioma (88 cores from 32 patients, from MesobanK UK), plus 14 mesothelioma cell lines (seven BAP1-mutant, seven with normal BAP1), clear cell renal cell carcinoma cell lines, and non-cancer lung fibroblasts and bronchial epithelial cells
• Exposure: No asbestos or fiber exposure was studied. The study examined loss of BAP1 function and treatment of cells with recombinant TRAIL. Asbestos is mentioned only as background.
• Main results:
  • In tumor tissue microarray cores, those without nuclear BAP1 (n = 46) had higher DR4 and DR5 expression than those with nuclear BAP1 (n = 42). The p-value was 0.024 for DR4 and 0.0092 for DR5.
  • BAP1-mutant mesothelioma cell lines had higher DR4 and DR5 levels than cell lines with normal BAP1. The p-value was 0.046 for DR4 and 0.009 for DR5.
  • Knocking down BAP1 in a mesothelioma cell line with normal BAP1 increased both DR4 and DR5 expression.
  • In two clear cell renal cell carcinoma cell lines with normal BAP1, BAP1 knockdown also increased DR4 and DR5 and increased sensitivity to recombinant TRAIL.
  • In non-cancer human lung fibroblasts and bronchial epithelial cells, BAP1 knockdown did not change DR4 or DR5 expression or sensitivity to recombinant TRAIL.
  • In BAP1-null mesothelioma cells, adding back normal BAP1 lowered DR4 and DR5 expression. An enzyme-inactive BAP1 mutant (C91A) did not.
  • YY1 was bound to BAP1 in mesothelioma and kidney cancer cells.
  • BAP1 and YY1 were both found at the promoter regions of DR4 and DR5 in cells given normal BAP1, but not in cells given the control vector.
  • YY1 knockdown increased sensitivity to recombinant TRAIL and to the DR5 agonist Medi3039 in mesothelioma and kidney cancer cells with normal BAP1.
  • In BAP1-mutant and BAP1-null mesothelioma cells, YY1 knockdown increased neither DR4 and DR5 expression nor TRAIL sensitivity.
• The authors' conclusion: The authors concluded that BAP1 and YY1 act at the DR4 and DR5 promoter regions to repress the transcription of these receptors, and that this requires BAP1's deubiquitinase (enzyme) activity.
• Limitations the authors state:
  • The authors noted that DR4 or DR5 levels alone could not explain TRAIL sensitivity in some cell lines with normal BAP1.
  • The authors did not investigate other cofactors that may direct BAP1 and YY1 to the DR4 and DR5 promoters.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Pleural Mesothelioma, Pleura, Necrosis, Apoptosis.

Related studies

• Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells — K.K. Kolluri, C. Alifrangis, et al. (2018)
• Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells — L. Su, G. Liu, et al. (2011)
• Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma — N. Kumar, D. Alrifai, et al. (2019)
• Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatin — L.L. Belyanskaya, T.M. Marti, et al. (2007)
• BAP1 and USP1 cooperate to regulate FANCD2 stability and cell proliferation in mesothelioma cells — K. Suzuki, S. Kiyonari, et al. (2026)
• Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer — T. Hirosawa, M. Ishida, et al. (2018)

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