Loss of BAP1 function leads to EZH2-dependent transformation Journal Article

Authors: LaFave, L. M.; Béguelin, W.; Koche, R.; Teater, M.; Spitzer, B.; Chramiec, A.; Papalexi, E.; Keller, M. D.; Hricik, T.; Konstantinoff, K.; Micol, J. B.; Durham, B.; Knutson, S. K.; Campbell, J. E.; Blum, G.; Shi, X.; Doud, E. H.; Krivtsov, A. V.; Chung, Y. R.; Khodos, I.; de Stanchina, E.; Ouerfelli, O.; Adusumilli, P. S.; Thomas, P. M.; Kelleher, N. L.; Luo, M.; Keilhack, H.; Abdel-Wahab, O.; Melnick, A.; Armstrong, S. A.; Levine, R. L.
Article Title: Loss of BAP1 function leads to EZH2-dependent transformation
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. © 2015 Macmillan Publishers Limited. All rights reserved.
Keywords: controlled study; unclassified drug; nonhuman; mouse; gene expression; animal experiment; animal model; methyltransferase; histone h3; gene repression; membrane protein; mesothelioma; myeloid progenitor cell; cell expansion; mutant; transcription factor ezh2; genetic transformation; polycomb repressive complex 2; bap1 protein; priority journal; article
Journal Title: Nature Medicine
Volume: 21
Issue: 11
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2015-11-01
Start Page: 1344
End Page: 1349
Language: English
DOI: 10.1038/nm.3947
PROVIDER: scopus
PMCID: PMC4636469
PUBMED: 26437366
Notes: Export Date: 2 December 2015 -- Source: Scopus
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