An overview of BAP1 biological functions and current therapeutics

Abstract

BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that was first identified in 1998. Germline loss-of-function variants in BAP1 are associated with a tumor predisposition syndrome with at least four cancers: uveal melanoma (UM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), and cutaneous melanoma (CM). Furthermore, somatic BAP1 mutations are important drivers for several cancers most notably UM, MMe, RCC, intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). Emerging evidence substantiates the fundamental role of BAP1 in suppressing cancer initiation and progression by tuning DNA damage repair, apoptosis, ferroptosis, immune response, Warburg phenomenon, and metastasis. Multiple treatment strategies such as poly (ADP-ribose) polymerase (PARP) inhibitors, EZH2 inhibitors, alkylating agents, and immunotherapy have been used as potential therapies for BAP1-mutated tumors. Although these agents showed promising results in BAP1-mutated tumors in preclinical studies, the results of most clinical trials are still dismal. The objectives of this review are to summarize the current state of knowledge regarding the biological functions of BAP1, the implications of these functions in tumorigenesis, and the current progress in BAP1-targeted therapy.