TitleLoss of BAP1 function leads to EZH2-dependent transformation.
Publication TypeJournal Article
Year of Publication2015
AuthorsLaFave, Lindsay M., B├ęguelin Wendy, Koche Richard, Teater Matt, Spitzer Barbara, Chramiec Alan, Papalexi Efthymia, Keller Matthew D., Hricik Todd, Konstantinoff Katerina, Micol Jean-Baptiste, Durham Benjamin, Knutson Sarah K., Campbell John E., Blum Gil, Shi Xinxu, Doud Emma H., Krivtsov Andrei V., Chung Young Rock, Khodos Inna, de Stanchina Elisa, Ouerfelli Ouathek, Adusumilli Prasad S., Thomas Paul M., Kelleher Neil L., Luo Minkui, Keilhack Heike, Abdel-Wahab Omar, Melnick Ari, Armstrong Scott A., and Levine Ross L.
JournalNat Med
Volume21
Issue11
Pagination1344-9
Date Published2015 Nov
ISSN1546-170X
KeywordsAnimals, Blotting, Western, Cell Line, Tumor, Chromatin Immunoprecipitation, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, HEK293 Cells, Histone Code, Histone-Lysine N-Methyltransferase, Histones, Humans, Immunoprecipitation, Leukemia, Mesothelioma, Methylation, Mice, Polycomb Repressive Complex 2, Real-Time Polymerase Chain Reaction, Repressor Proteins, Tumor Suppressor Proteins, Ubiquitin Thiolesterase
Abstract

<p>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. </p>

DOI10.1038/nm.3947
Alternate JournalNat Med
PubMed ID26437366
PubMed Central IDPMC4636469
Grant ListR01 CA173636 / CA / NCI NIH HHS / United States
R01 GM096056 / GM / NIGMS NIH HHS / United States
F31 CA180642 / CA / NCI NIH HHS / United States
R01 CA187109 / CA / NCI NIH HHS / United States
CA172636 / CA / NCI NIH HHS / United States
2R01GM096056 / GM / NIGMS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
P30 CA060553 / CA / NCI NIH HHS / United States
R01 GM120570 / GM / NIGMS NIH HHS / United States
R01 CA169784 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States