Roles and mechanisms of BAP1 deubiquitinase in tumor suppression

Our plain-English summary of Roles and mechanisms of BAP1 deubiquitinase in tumor suppression, by L. Masclef, O. Ahmed, B. Estavoyer, et al (Cell Death and Differentiation, 2021).

The study

• Authors: L. Masclef, O. Ahmed, B. Estavoyer, B. Larrivée, N. Labrecque, A. Nijnik, E.B. Affar
• Journal: Cell Death and Differentiation
• Published: 2021;28(2):606-625
• Type of article: Review
• Cited by: 149 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The BAP1 gene has emerged as a major tumor suppressor mutated with various frequencies in numerous human malignancies, including uveal melanoma, malignant pleural mesothelioma, clear cell renal cell carcinoma, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and thymic epithelial tumors. BAP1 mutations are also observed at low frequency in other malignancies including breast, colorectal, pancreatic, and bladder cancers. BAP1 germline mutations are associated with high incidence of mesothelioma, uveal melanoma, and other cancers, defining the "BAP1 cancer syndrome." Interestingly, germline BAP1 mutations constitute an important paradigm for gene-environment interactions, as loss of BAP1 predisposes to carcinogen-induced tumorigenesis. Inactivating mutations of BAP1 are also identified in sporadic cancers, denoting the importance of this gene for normal tissue homeostasis and tumor suppression, although some oncogenic properties have also been attributed to BAP1. BAP1 belongs to the deubiquitinase superfamily of enzymes, which are responsible for the maturation and turnover of ubiquitin as well as the reversal of substrate ubiquitination, thus regulating ubiquitin signaling. BAP1 is predominantly nuclear and interacts with several chromatin-associated factors, assembling multi-protein complexes with mutually exclusive partners. BAP1 exerts its function through highly regulated deubiquitination of its substrates. As such, BAP1 orchestrates chromatin-associated processes including gene expression, DNA replication, and DNA repair. BAP1 also exerts cytoplasmic functions, notably in regulating Ca2+ signaling at the endoplasmic reticulum. This DUB is also subjected to multiple post-translational modifications, notably phosphorylation and ubiquitination, indicating that several signaling pathways tightly regulate its function. Recent progress indicated that BAP1 plays essential roles in multiple cellular processes including cell proliferation and differentiation, cell metabolism, as well as cell survival and death. In this review, we summarize the biological and molecular functions of BAP1 and explain how the inactivation of this DUB might cause human cancers. We also highlight some of the unresolved questions and suggest potential new directions.

In plain English

This article is a review. The authors summarized published laboratory, animal and human genetic research on BAP1, a gene whose protein removes ubiquitin tags from other proteins, and reported no new data of their own. Drawing on earlier studies, they described BAP1 as a tumor suppressor involved in gene control, DNA repair, cell growth, cell death and metabolism. Citing other studies, they reported BAP1 mutations in near 60% of malignant pleural mesothelioma, a cancer they called often associated with asbestos exposure. They reported such mutations in about 25% of malignant peritoneal mesothelioma, which they called usually not associated with asbestos exposure, and in about 40% of patients with uveal melanoma (an eye cancer). They linked inherited BAP1 mutations, the BAP1 cancer syndrome, to a high risk of uveal melanoma, pleural mesothelioma, clear cell renal cell carcinoma and other cancers. Cited mouse studies found that mice with one faulty Bap1 copy were more susceptible to asbestos-induced pleural mesothelioma than normal mice. No asbestos fiber type was named. The authors noted it remains largely unclear why BAP1 loss causes cancer only in some cell types.

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: narrative review of published research on the BAP1 gene
• Who was studied: No new study population. The review covered published cell, mouse, frog (Xenopus) and human tumor and family genetic studies of BAP1.
• Exposure: Loss or mutation of the BAP1 gene, either inherited (germline) or acquired in tumors. Asbestos appears only in the description of malignant pleural mesothelioma and in cited mouse studies. No fiber type is named.
• Main results:
  • Citing other studies, the authors reported that malignant pleural mesothelioma tumors carry BAP1 mutations in near 60% of cases. Combined BAP1, NF2 and CDKN2A mutations occur in about 34% of these tumors.
  • Citing another study, the authors reported BAP1 mutations in about 25% of malignant peritoneal mesothelioma cases. They described this rare cancer as usually not associated with asbestos exposure.
  • Citing another study, the authors reported that BAP1 is mutated in about 40% of patients with uveal melanoma.
  • The authors reported that inherited (germline) BAP1 mutations define the BAP1 cancer syndrome, which carries a high risk of uveal melanoma, malignant pleural mesothelioma, clear cell renal cell carcinoma and other cancers.
  • Citing two mouse studies, the authors reported that mice with heterozygous Bap1 mutations were more susceptible to asbestos-induced malignant pleural mesothelioma than wild-type mice. The authors wrote that these findings raised a note of caution about exposing people with germline BAP1 mutations to even minimal doses of carcinogens.
  • From the reviewed laboratory studies, the authors described BAP1 as promoting DNA repair and genomic integrity.
• The authors' conclusion: The authors concluded that BAP1 regulates several cell processes and acts as a tumor suppressor. They stated it is still largely unclear why loss of BAP1 leads to cancer only in some cell types and tissues.
• Limitations the authors state:
  • The authors stated that the proposed oncogenic (cancer-promoting) properties of BAP1 need confirmation in mouse models with disease-like protein levels.
  • The authors stated that more studies are needed to show how differences between cell types in susceptibility to cell death affect BAP1-related cancer.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Pleural Mesothelioma, Carcinoma, Germline Mutation, Mesothelioma, BAP1 Tumor Predisposition Syndrome, Carcinogenesis.

Related studies

• Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis — C. Luchini, N. Veronese, et al. (2016)
• The spectrum of tumors harboring BAP1 gene alterations — Y. Laitman, J. Newberg, et al. (2021)
• BAP1 and cancer — M. Carbone, H. Yang, et al. (2013)
• A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma — K.A. Wadt, L.G. Aoude, et al. (2015)
• Histologically Diverse BAP1-Deficient Melanocytic Tumors in a Patient With BAP1 Tumor Predisposition Syndrome — A. Louw, J. Creaney, et al. (2020)
• BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation — A. Bononi, C. Giorgi, et al. (2017)

Browse more research in Cell Death and Differentiation, or return to medical research.