A mechanism for the tissue specificity

Transl Cancer Res 2019 | http://dx.doi. org/10.21037/tcr.2019. 06.41 Cancer predisposition syndromes are caused by inherited mutations in tumor suppressor genes. Remarkably, despite the presence of the faulty tumor suppressor gene in virtually every cell in the body, individuals with a cancer predisposition syndrome develop tumors in specific organs but not others. The underlying mechanisms of the tissue specificity varies depending on the mutated tumor suppressor gene. A recent study by He et al. (1) sheds new light on the tissue specificity of the BAP1 cancer syndrome, which is caused by inheritance of a germline mutation in the tumor suppressor gene BAP1. This familial cancer predisposition syndrome exhibits an increased incidence of specific types of cancers, including mesothelioma, melanocytic tumors, uveal melanoma, renal cell carcinoma and others (2-9). He et al. demonstrate that conditional Bap1 inactivation in mice resulted in cell death in many cell types, but not in mesothelium and melanocytes, the same cell types from which tumors arise in BAP1 mutation carriers in humans. Through experiments using CRISPRbased genetic screens, RNA sequencing (RNA-seq), and chromatin immunoprecipitation (ChIP), the authors provide new insight into the mechanism by which BAP1 loss causes apoptosis in certain tissues but not others. BAP1 is a classic tumor suppressor gene that follows Knudson’s two hit hypothesis, in which carriers of a heterozygous mutation undergo loss of heterozygosity (LOH) to lose the functional allele in tumors. Paradoxically, despite the fact that BAP1 loss promotes tumorigenesis, BAP1 inactivation causes cell death in many cell types. He et al. showed that Bap1 knockout in mouse embryonic stem (ES) cells, fibroblasts, and keratinocytes caused cell death through the intrinsic apoptosis pathway (1), which is mediated by Bax/Bak oligomerization. Induced Bap1 inactivation in adult mice also caused Bax/Bakdependent apoptosis in the liver and pancreas, leading to liver damage and pancreatic atrophy. Interestingly, Bap1 inactivation did not cause apoptosis in mesothelium and melanocytes. Because surviving BAP1 inactivation is prerequisite for development of BAP1-deficient tumors, the lack of apoptosis after Bap1 inactivation would provide an explanation for why tumors develop in mesothelium and melanocytes but not other cell types. The BAP1 gene encodes a deubiquitinase, an enzyme that reverses post-translational modification of proteins with ubiquitin. BAP1 inactivation can occur as a consequence of either missense mutations in the ubiquitin C-terminal hydrolase (UCH) domain in the N-terminal region, or frameshift or nonsense mutations that cause truncation of the BAP1 protein. Because the C-terminal region encodes nuclear localization signals and a regulatory domain necessary for activation of the UCH domain, the truncated proteins often mislocalize in the cytoplasm or lack deubiquitinase activity. Among the substrates that have been reported to be deubiquitinated by BAP1, deubiquitination of histone H2A is best characterized. Histone H2A is monoubiquitinated at Lys119 by the ubiquitin ligase polycomb repressive complex 1 (PRC1) and deubiquitinated by BAP1 (10). Because H2AK119ub is generally a repressive mark for transcription, BAP1 inactivation is expected to cause PRC1-dependent gene repression. Editorial Commentary