Bap1 loss decreases H4K20me1, increases H3K27me3, and induces EZH2-dependent proliferation.
Major finding: Bap1 loss decreases H4K20me1, increases H3K27me3, and induces EZH2-dependent proliferation.
Concept: BAP1 and ASXL1 form a deubiquitinating complex, but BAP1 has ASXL1-independent functions in cancer.
Impact: EZH2 inhibitors have promise as novel therapeutics for BAP1-mutant tumors including mesothelioma.
BAP1 and ASXL1 are tumor suppressors that form a polycomb deubiquitinase complex that deubiquitinates histone 2A lysine 119. However, they are mutated in distinct types of cancer, suggesting independent roles in malignant transformation. LaFave and colleagues showed that genetic deletion of Bap1 in mice led to myeloproliferative disease and increased proliferation of myeloid progenitor cells. RNA-sequencing analysis of Bap1- and Asxl1-knockout myeloid progenitor cells indicated significant overlap between the differentially expressed genes; however, Bap1 and Asxl1 deletion had inverse effects on many genes. Further, chromatin immunoprecipitation sequencing analysis indicated a global increase in trimethylated H3K27 (H3K27me3) in Bap1-knockout mice, whereas ASXL1 is known to reduce H3K27me3. The increase in H3K27me3 resulting from Bap1 deletion was associated with repression of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)–dependent genes, and Ezh2 deletion reduced H3K27me3 levels in Bap1-deficient mice compared with control mice. Genetic deletion or pharmacologic inhibition of EZH2 also reversed the myeloid malignancy induced by Bap1 deletion, resulting in reduced splenomegaly, leukocytosis, and anemia, indicating that EZH2 is essential for myeloid transformation in Bap1-deficient cells. Mechanistically, BAP1 and the atypical polycomb protein L3MBTL2 co-occupied the EZH2 locus, thereby increasing H4K20 monomethylation (H4K20me1) and repressing EZH2 expression. Consistent with this finding, expression of the H4K20me1 methyltransferase SET domain–containing lysine methyltransferase 8 diminished EZH2 expression and suppressed the growth of BAP1-mutant cells. These findings have clinical implications in mesotheliomas, which frequently harbor BAP1 mutations and, based on The Cancer Genome Atlas data, have increased EZH2 expression. Treatment of BAP1-mutant mesothelioma cells and xenografts with the EZH2 inhibitor EPZ011989 reduced tumor growth, invasion, and pulmonary metastasis. Together, these findings suggest that EZH2 inhibition may be an effective therapy in BAP1-mutant cancers, and, as EZH2 inhibitors are currently in clinical trials, these findings may be quickly translated to patient care.