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 Khodos; Elisa 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

doi:10.1038/nm.3947

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

Research output: Contribution to journal › Article › peer-review

273 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 language	English (US)
Pages (from-to)	1344-1349
Number of pages	6
Journal	Nature Medicine
Volume	21
Issue number	11
DOIs	https://doi.org/10.1038/nm.3947
State	Published - Nov 1 2015
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.3947

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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

Lafave, LM, Béguelin, W, Koche, R, Teater, M, Spitzer, B, Chramiec, A, Papalexi, E, Keller, MD, Hricik, T, Konstantinoff, K, Micol, JB, Durham, B, Knutson, SK, Campbell, JE, Blum, G, Shi, X, Doud, EH, Krivtsov, AV, Chung, YR, Khodos, I, De Stanchina, E, Ouerfelli, O, Adusumilli, PS, Thomas, PM, Kelleher, NL, Luo, M, Keilhack, H, Abdel-Wahab, O, Melnick, A, Armstrong, SA & Levine, RL 2015, 'Loss of BAP1 function leads to EZH2-dependent transformation', Nature Medicine, vol. 21, no. 11, pp. 1344-1349. https://doi.org/10.1038/nm.3947

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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.}",

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AU - Lafave, Lindsay M.

AU - Béguelin, Wendy

AU - Koche, Richard

AU - Teater, Matt

AU - Spitzer, Barbara

AU - Chramiec, Alan

AU - Papalexi, Efthymia

AU - Keller, Matthew D.

AU - Hricik, Todd

AU - Konstantinoff, Katerina

AU - Micol, Jean Baptiste

AU - Durham, Benjamin

AU - Knutson, Sarah K.

AU - Campbell, John E.

AU - Blum, Gil

AU - Shi, Xinxu

AU - Doud, Emma H.

AU - Krivtsov, Andrei V.

AU - Chung, Young Rock

AU - Khodos, Inna

AU - De Stanchina, Elisa

AU - Ouerfelli, Ouathek

AU - Adusumilli, Prasad S.

AU - Thomas, Paul M.

AU - Kelleher, Neil L.

AU - Luo, Minkui

AU - Keilhack, Heike

AU - Abdel-Wahab, Omar

AU - Melnick, Ari

AU - Armstrong, Scott A.

AU - Levine, Ross L.

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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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ER -

Loss of BAP1 function leads to EZH2-dependent transformation

Abstract

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