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Loss of BAP1 function leads to EZH2-dependent transformation


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.

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Figure 1: Bap1 deletion results in increased levels of H3K27me3.
Figure 2: Proliferation induced by Bap1 deletion is rescued by the loss of Ezh2.
Figure 3: BAP1 loss leads to increased PRC2 expression and decreased H4K20me1 levels.
Figure 4: BAP1-mutant mesothelioma models are sensitive to EZH2 inhibition.

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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.

Author information




L.M.L., O.A.-W. and R.L.L. designed the study. L.M.L., W.B., A.C., E.P., M.D.K., K.K., J.-B.M., I.K., E.H.D., X.S., Y.R.C. and O.A.-W. performed the experiments. L.M.L., W.B., R.K., M.T., B.S., T.H., A.C. and O.A.-W. performed ChIP-and RNA-Seq, sequencing and subsequent downstream analyses. B.D., S.K.K., J.E.C., G.B., E.d.S., O.O., P.S.A., P.M.T., N.L.K., M.L., H.K., A.M., S.A.A. and R.L.L. participated in data analysis and discussions. L.M.L. and R.L.L. prepared the manuscript with input from all authors.

Corresponding author

Correspondence to Ross L Levine.

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Competing interests

S.K.K., J.E.C. and H.K. are employees of Epizyme, Inc. S.A.A. is a consultant for Epizyme, Inc.

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LaFave, L., Béguelin, W., Koche, R. et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med 21, 1344–1349 (2015).

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