@article{67f1fed5414643f69b49ec3ef6091893,
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.",
author = "Lafave, {Lindsay M.} and Wendy B{\'e}guelin and Richard Koche and Matt Teater and Barbara Spitzer and Alan Chramiec and Efthymia Papalexi and Keller, {Matthew D.} and Todd Hricik and Katerina Konstantinoff and Micol, {Jean Baptiste} and Benjamin Durham and Knutson, {Sarah K.} and Campbell, {John E.} and Gil Blum and Xinxu Shi and Doud, {Emma H.} and Krivtsov, {Andrei V.} and Chung, {Young Rock} and Inna Khodos and {De Stanchina}, Elisa and Ouathek Ouerfelli and Adusumilli, {Prasad S.} and Thomas, {Paul M.} and Kelleher, {Neil L.} and Minkui Luo and Heike Keilhack and Omar Abdel-Wahab and Ari Melnick and Armstrong, {Scott A.} and Levine, {Ross L.}",
note = "Funding Information: This work was supported by the Pershing Square Sohn Prize (R.L.L.), by grant 2R01GM096056 (M.L.), by grant CA172636 (R.L.L. and A.M.) and by grant F31 CA180642-02 (L.M.L.). Work in the Memorial Sloan Kettering Cancer Center (MSKCC) Core facilities that supported these studies is supported by P30 CA008748. R.L.L. is a Leukemia and Lymphoma Society Scholar. We would like to thank V. Rotter (Weizmann Institute of Science, Israel), X. Jiang (MSKCC), and M. Ladanyi (MSKCC) for generously providing plasmids for this work. We would like to thank D. Scheinberg (MSKCC) for generously sharing the mesothelioma cell lines used in this work. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",
year = "2015",
month = nov,
day = "1",
doi = "10.1038/nm.3947",
language = "English (US)",
volume = "21",
pages = "1344--1349",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "11",
}
