BAP1: Not just a BRCA1-associated protein

Abstract

BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase that has been established as a tumor suppressor, utilizing its deubiquitinating activity to regulate a number of processes including DNA damage repair, cell cycle control, chromatin modification, programmed cell death, and the immune response. Mutations in the BAP1 gene commonly result in a number of aggressive cancers; predominantly uveal melanoma, malignant mesothelioma, renal cell carcinoma, and cutaneous melanoma. Importantly, germline mutations in the BAP1 gene have been established as a novel tumor predisposition syndrome, conferring an increased risk of hereditary, early-onset cancers. Current treatment options for cancers with BAP1 alterations are limited to standard therapies. However, several therapeutic avenues have been proposed to specifically target BAP1 alterations in cancer. Molecularly targeted approaches include histone deacetylase inhibitors and EZH2 inhibitors to target the role of BAP1 in chromatin modification and transcriptional regulation, respectively. PARP inhibitors and platinum chemotherapy agents have the potential to target BAP1-altered tumors, due to the role of BAP1 in DNA damage repair. Lastly, emerging reports suggest that BAP1-alterations in cancer confer distinct immunogenic phenotypes that may be particularly susceptible to novel cancer immunotherapies. This review aims to present a concise and up to date report on the BAP1 gene in cancer, surveying its functional roles, characteristics and clinical manifestations. Furthermore, we highlight the established and emerging therapeutic options for BAP1-mutated cancers.

Emerging multifaceted roles of BAP1 complexes in biological processes

“…To date, the BAP1 complex was discovered for over two decades now and has been actively investigated throughout the years, with emerging studies unfolding its complex nature 74 . As a general transcriptional activator and a major deubiquitinase of histone H2AK119, the BAP1 complex establishes an epigenetic balance with the PRC1 complex to determine the “switching on/off” of transcriptional activity, ultimately affecting targeted gene expression.…”

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors

“…Indeed, the difference in the incidence of BAP1 mutations between the anti-PD1/L1 and the anti-PD1 + anti-CTLA4 group may be particularly relevant. BAP1 is a multifunctional tumor suppressor, and BAP1 mutations in UM are associated with activation of regulatory immune cells and an imunosuppressive tumor microenvironment [ 47 , 48 ]. This could contribute to resistance to ICI and differences in clinical outcomes; however, this is not well understood and is still being elucidated.…”

Development of a Metastatic Uveal Melanoma Prognostic risk Score (MUMPS) for use in patients receiving immune checkpoint inhibitors

“…The difference in the incidence of BAP1 mutations between the anti-PD1/L1 and the anti-PD1 + anti-CTLA4 group is relevant. BAP1 is a multifunctional tumor suppressor and BAP1 mutations in UM are associated with activation of regulatory immune cells and an immunosuppressive tumor microenvironment [45, 46]. This could contribute to resistance to ICI and differences in clinical outcomes between our cohort; however, this is not well understood and is still being elucidated.…”