BAP1 in cancer: epigenetic stability and genome integrity

Abstract

Mutations in BAP1 have been identified in a hereditary cancer predisposition syndrome and in sporadic tumours. Individuals carrying familiar BAP1 monoallelic mutations display hypersusceptibility to exposure-associated cancers, such as asbestos-driven mesothelioma, thus BAP1 status has been postulated to participate in gene-environment interaction. Intriguingly, BAP1 functions display also a high degree of tissue dependency, associated to a peculiar cancer spectrum and cell types of specific functions. Mechanistically, BAP1 functions as an ubiquitin carboxy-terminal hydrolase (UCH) and controls regulatory ubiquitination of histones as well as degradative ubiquitination of a range of protein substrates. In this article we provide an overview of the most relevant findings on BAP1, underpinning its tissue specific tumour suppressor function. We also discuss the importance of its epigenetic role versus the control of protein stability in the regulation of genomic integrity.

BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13

“…Moreover, as C. elegans has orthologs for BRCA1 and BRAD1 ( brc-1 and brd-1 , respectively) [ 51 , 52 ], our model would help to study the mechanisms of controversial functional links between BAP1 and the BRCA1-BRAD1 complex, which play a critical role in DNA repair and homologous recombination, both in mammals [ 13 ] and C. elegans [ 53 , 54 ]. Since inactivation of the proteasome by RNAi or use of inhibitors produces aberrant nuclei in C. elegans germline [ 43 , 50 ] and BAP1 has a regulatory function on ubiquitination of histones [ 55 ], genome instability would be the “hallmark of cancer” behind the BAP1 alterations. Interestingly, although the specific mechanism of carcinogenesis induced by asbestos in MPM is still unclear, it has been proposed that asbestos causes genome instability [ 56 ] and chromosomal segregation defects [ 57 ].…”

Mass Spectrometry-Based Profiling of Histone Post-Translational Modifications in Uveal Melanoma Tissues, Human Melanocytes, and Uveal Melanoma Cell Lines – A Pilot Study

“…A BAP1 mutation has been previously associated with increased levels of H3K27me3. 11 , 54 , 55 Although this finding is often reported, Campagne et al did not observe a global effect of BAP1 knockout on the overall levels of H3K4me2 and H3K27me3. 56 In our study, an increase of H3K27me3 was only observed in one of the BAP1-mutated cell lines.…”

Second Primary Cancers in a Population-Based Mesothelioma Registry

“…Several findings have suggested a potential role for BAP1 in the carcinogenesis of numerous malignancies [ 32 , 33 , 34 , 35 ]. BAP1 is an oncosuppressor protein that acts as a deubiquitinase and is involved in gene expression and chromatin regulation [ 34 , 35 , 36 ]; it is commonly inactivated in mesotheliomas [ 7 , 37 , 38 , 39 , 40 ]. Germline BAP1 mutations underpin the BAP1 tumor predisposition syndrome (BAP1-TPDS).…”

“…Some recent studies have suggested that BAP1 mutations may interact with exposure to carcinogens, such as asbestos. This gene–environment interaction is a possible carcinogenic mechanism [ 34 , 36 , 41 , 42 ]. Therefore, we evaluated the frequency of asbestos-related and BAP1 syndrome-related malignancies among SPC patients.…”