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 H. Durham,Sarah K. Knutson,John 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 +30 more
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TL;DR: It is demonstrated 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 repression complex 2 (PRC2) targets.
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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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Citations
Histone H2AK119 Mono-Ubiquitination Is Essential for Polycomb-Mediated Transcriptional Repression.
Simone Tamburri,Elisa Lavarone,Daniel Fernández-Pérez,Daniel Fernández-Pérez,Eric Conway,Marika Zanotti,Daria Manganaro,Diego Pasini,Diego Pasini +8 more
TL;DR: Using a fully catalytic inactive RING1B mutant, it is demonstrated that H2AK119ub1 deposition is essential to maintain PcG-target gene repression in embryonic stem cells (ESCs) and overall, the data place H3K27me3 deposition as a central hub that mounts P cG repressive machineries to preserve cell transcriptional identity.
302
The roles of Polycomb repressive complexes in mammalian development and cancer.
Andrea Piunti,Ali Shilatifard +1 more
TL;DR: A review of the biochemical and molecular functions of these new PcG complex variants, and how their epigenetic activities are involved in mammalian development and cancer, can be found in this paper.
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PRC2 is high maintenance
Jia Ray Yu,Jia Ray Yu,Chul Hwan Lee,Chul Hwan Lee,Ozgur Oksuz,Ozgur Oksuz,James M. Stafford,James M. Stafford,Danny Reinberg,Danny Reinberg +9 more
TL;DR: In this review, Yu et al. discuss the recent advances in knowledge of the Polycomb-repressive complex 2 (PRC2) in mammalian systems and discuss important discoveries on Polycomb function derived from model organisms in the context of understanding mammalian PRC2 function.
ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma
Arnaud Scherpereel,Isabelle Opitz,Thierry Berghmans,Ioannis Psallidas,Markus Glatzer,David Rigau,Philippe Astoul,Servet Bölükbas,Jeanette Boyd,Johan Coolen,Charlotte De Bondt,Dirk De Ruysscher,Valérie Durieux,Corinne Faivre-Finn,Dean A. Fennell,Françoise Galateau-Sallé,Laurent Greillier,Mir Ali Hoda,Walter Klepetko,Aude Lacourt,Phil McElnay,Nick A Maskell,Luciano Mutti,Jean-Claude Pairon,Paul Van Schil,Jan P. van Meerbeeck,David A. Waller,Walter Weder,Giuseppe Cardillo,Paul Martin Putora,Paul Martin Putora +30 more
TL;DR: It is emphasised that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres, because of limited data on the best combination treatment.
237
Targeting EZH2 in cancer therapy.
Makoto Yamagishi,Kaoru Uchimaru +1 more
TL;DR: The present review introduces recent outstanding progress pertaining to Enhancer of zeste homolog 2 (EZH2), especially regarding its mode of action as a master regulator of chromatin, and provides molecular-based evidence for targeting EZh2 in cancer therapy.
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