Loss of BAP1 function leads to EZH2-dependent transformation

Abstract

Introductory Paragraph BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated Ezh2 expression, and enhanced repression of Polycomb Repressive Complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of Bap1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in EZH2 transcriptional regulation, expression of SETD8, the H4K20me1 methyltransferase, reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Further, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.

Novel systemic therapy against malignant pleural mesothelioma

“…While these clinical studies demonstrate lack of benefit after pharmacologic inhibition of histone deacetylase to target epigenetic regulation in MPM, a preclinical study identified synthetic lethality with pharmacologic inhibition of enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) in MPM cells lacking Bap1 (124). A phase II study evaluating efficacy of the EZH2 inhibitor tazemetostat in patients with both Bap1-deficient and wild-type relapsed or refractory MPM is currently ongoing (clinicaltrials.gov NCT02860286).…”

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

“…Hematopoieticspecific conditional loss of Bap1 resulted in retention of monoubiquitinated H2AK119 and decreased expression levels of transcriptional regulator host cell factor-1 (HCF1) and OGT, leading to MDS/MPN-like disease in vivo [98]. However, in contrast to Asxl1 loss, Bap1 deletion was shown to increase Ezh2 and H3K27me3 levels and enhance repression of PRC2 targets, sensitizing BAP1-deficient mesothelioma to pharmacologic EZH2 inhibition [99]. These data indicate that ASXL1 and BAP1 loss may function in independent manner in myeloid transformation.…”

Targeting the epigenome in malignant pleural mesothelioma

“…BAP1 mutations decreased occupancy of BAP1 as well as L3MBTL2 within the EZH2 promoter. Relative to MPM cells expressing BAP1, MPM cells with BAP1 mutations were markedly more sensitive to pharmacologic inhibitors of EZH2 in-vitro and in-vivo (92), suggesting that BAP1 mutations render MPM cells addicted to PRC-2.…”

“…Conceivably, global and promoter-specific PRC-2 marks, DNA methylation, micro-RNA and gene expression profiles, as well as responses to biochemical or pharmacologic inhibition of PRC-2 activity may be contingent on BAP1 mutation status as well as magnitude of EZH2 over-expression in MPM. In a series of elegant experiments, LaFave et al (92) observed that BAP1 mutations, which typically result in loss of protein expression, increased EZH2 as well as SUZ12 expression in MPM cells. Up-regulation of EZH2 in BAP1 mutant cells was associated with reduced levels of H4K2Me1, as well as decreased occupancy of L3MBTL2 (an atypical polycomb protein which recognizes this repressive histone mark) within the EZH2 promoter (96,97).…”

“…Given the frequency and negative prognostic impact of EZH2 over-expression in MPM (90,92), PRC-2 has emerged as a major therapeutic target in these neoplasms-particularly those with BAP1 mutations. Whereas DZNep is not available for clinical trials, several potent and specific inhibitors of EZH2 activity are in early clinical development.…”