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.

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Acknowledgements

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

Author notes

    • Wendy Béguelin
    •  & Richard Koche

    These authors contributed equally to this work.

Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Lindsay M LaFave
    • , Efthymia Papalexi
    • , Matthew D Keller
    • , Todd Hricik
    • , Katerina Konstantinoff
    • , Jean-Baptiste Micol
    • , Benjamin Durham
    • , Young Rock Chung
    • , Omar Abdel-Wahab
    •  & Ross L Levine
  2. Gerstner Sloan Kettering School of Biomedical Sciences, New York, New York, USA.

    • Lindsay M LaFave
  3. Department of Hematology/Oncology, Weill Cornell Medical College, New York, New York, USA.

    • Wendy Béguelin
    • , Matt Teater
    •  & Ari Melnick
  4. The Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Richard Koche
    • , Alan Chramiec
    • , Andrei V Krivtsov
    • , Scott A Armstrong
    •  & Ross L Levine
  5. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Richard Koche
    •  & Scott A Armstrong
  6. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Barbara Spitzer
    •  & Scott A Armstrong
  7. Epizyme, Inc., Cambridge, Massachusetts, USA.

    • Sarah K Knutson
    • , John E Campbell
    •  & Heike Keilhack
  8. Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.

    • Gil Blum
    •  & Minkui Luo
  9. Tri-Institutional Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Gil Blum
  10. Chemical Synthesis Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Xinxu Shi
    •  & Ouathek Ouerfelli
  11. Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.

    • Emma H Doud
    • , Paul M Thomas
    •  & Neil L Kelleher
  12. Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Inna Khodos
    •  & Elisa de Stanchina
  13. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Prasad S Adusumilli
  14. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Omar Abdel-Wahab
    •  & Ross L Levine

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Contributions

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.

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.

Corresponding author

Correspondence to Ross L Levine.

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DOI

https://doi.org/10.1038/nm.3947

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