Loss of BAP1 function leads to EZH2-dependent transformation

Lindsay M. Lafave, Wendy Béguelin, Richard Koche, Matt Teater, Barbara Spitzer, Alan Chramiec, Efthymia Papalexi, Matthew D. Keller, Todd Hricik, Katerina Konstantinoff, Jean Baptiste Micol, Benjamin Durham, Sarah K. Knutson, John E. Campbell, Gil Blum, Xinxu Shi, Emma H. Doud, Andrei V. Krivtsov, Young Rock Chung, Inna KhodosElisa De Stanchina, Ouathek Ouerfelli, Prasad S. Adusumilli, Paul M. Thomas, Neil L. Kelleher, Minkui Luo, Heike Keilhack, Omar Abdel-Wahab, Ari Melnick, Scott A. Armstrong, Ross L. Levine*

*Corresponding author for this work

Research output: Contribution to journalArticle

138 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1344-1349
Number of pages6
JournalNature Medicine
Volume21
Issue number11
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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., ... Levine, R. L. (2015). Loss of BAP1 function leads to EZH2-dependent transformation. Nature Medicine, 21(11), 1344-1349. https://doi.org/10.1038/nm.3947