Intrinsic apoptosis shapes the tumor spectrum linked to inactivation of the deubiquitinase BAP1

Abstract

Tissue specificity of tumor suppression It is well known that the loss of tumor suppressor genes leads to a limited subset of cancers in specific tissues. But why just those tissues? He et al. found a relatively simple explanation for how this tissue selectivity works for the tumor suppressor BAP1 using a mouse model of BAP1-induced cancer. In most cells, loss of BAP1 caused cell death or apoptosis. But in the tissues that formed tumors, differences in the regulation of genes with antiapoptotic effects allowed the cells to survive, even though BAP1 was lost. At least for this one tumor suppressor, its inactivation would normally cause a cell to die; however, this mechanism is absent in a subset of tissues, allowing the cells to proliferate and cause a tumor. Science , this issue p. 283

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

“…BAP1 mutations were discovered in intrahepatic cholangiocarcinoma and hepatocellular carcinoma ( Masclef et al, 2021 ). Moreover, a previous study assumed that BAP1 modulated gene expression by inhibiting H2A ubiquitination, and BAP1 inactivation led to apoptosis of fibroblasts and liver tissue in mice ( Table 1 ; Figure 2 ) ( He et al, 2019 ). Therefore, there might be a possibility that H2A ubiquitination plays a role in tumorigenesis.…”

A mechanism for the tissue specificity in BAP1 cancer syndrome

“…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 ).…”

“…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/Bak-dependent apoptosis in the liver and pancreas, leading to liver damage and pancreatic atrophy.…”

“…To gain more insight into the apoptosis that follows Bap1 inactivation, He et al performed a genome-wide CRISPR-Cas9 screen and identified Rnf2 as a gene that promotes the death of Bap1 knockout MEFs ( 1 ). Rnf2 is a ubiquitin E3 ligase component of PRC1, responsible for the deposition of the H2AK119ub mark.…”

“…In stark contrast to ES cells, however, primary melanocytes and mesothelial cells maintained normal levels of Bcl2 and Mcl1 proteins after Bap1 inactivation and did not undergo apoptosis ( 1 ). He et al found that melanocytes and mesothelial cells had minimal Rnf2 binding to the Bcl2 promoter regardless of the Bap1 gene status.…”