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

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Science  19 Apr 2019:
Vol. 364, Issue 6437, pp. 283-285
DOI: 10.1126/science.aav4902

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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

Abstract

Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example, BAP1 encodes a widely expressed deubiquitinase for histone H2A, but germline mutations are predominantly associated with uveal melanomas and mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient cells by suppressing expression of the prosurvival genes Bcl2 and Mcl1. In contrast, BAP1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Mitf. Thus, BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program.

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