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Nat Med. 2015 Nov;21(11):1344-9. doi: 10.1038/nm.3947. Epub 2015 Oct 5.

Loss of BAP1 function leads to EZH2-dependent transformation.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Gerstner Sloan Kettering School of Biomedical Sciences, New York, New York, USA.
3
Department of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA.
4
The Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
7
Epizyme, Inc., Cambridge, Massachusetts, USA.
8
Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Tri-Institutional Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
10
Chemical Synthesis Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
11
Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
12
Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
13
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
14
Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Abstract

The tumor suppressors 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 in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels 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 the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.

PMID:
26437366
PMCID:
PMC4636469
DOI:
10.1038/nm.3947
[Indexed for MEDLINE]
Free PMC Article

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