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
Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer
Michele Carbone,J. William Harbour,James Brugarolas,Angela Bononi,Ian Pagano,Anwesha Dey,Thomas Krausz,Harvey I. Pass,Haining Yang,Giovanni Gaudino +9 more
TL;DR: Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm,Where it regulates cell death and mitochondrial metabolism.
Chemical and Biochemical Perspectives of Protein Lysine Methylation.
Minkui Luo,Minkui Luo +1 more
TL;DR: This review will focus on chemical and biochemical aspects in addition, recognition, and removal of this posttranslational mark of protein lysine methylation.
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An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation.
George P. Souroullas,William R. Jeck,Joel S. Parker,Jeremy M. Simon,Jie Yu Liu,Joshiawa Paulk,Jessie Xiong,Kelly S. Clark,Yuri Fedoriw,Jun Qi,Christin E. Burd,James E. Bradner,Norman E. Sharpless +12 more
TL;DR: It is suggested that Ezh2Y641F induces lymphoma and melanoma through a vast reorganization of chromatin structure, inducing both repression and activation of polycomb-regulated loci.
Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2.
Lian Dee Ler,Sujoy Ghosh,Xiaoran Chai,Aye Aye Thike,Hong Lee Heng,Ee Yan Siew,Sucharita Dey,Liang Kai Koh,Jing Quan Lim,Weng Khong Lim,Swe Swe Myint,Jia Liang Loh,Pauline Ong,Xin Xiu Sam,Dachuan Huang,Tony Kiat Hon Lim,Puay Hoon Tan,Sanjanaa Nagarajan,Christopher Cheng,Henry Ho,Lay Guat Ng,John Shyi Peng Yuen,Po-Hung Lin,Cheng-Keng Chuang,Ying-Hsu Chang,Wen-Hui Weng,Steven G. Rozen,Patrick Tan,Caretha L. Creasy,See-Tong Pang,Michael T. McCabe,Song Ling Poon,Bin Tean Teh +32 more
TL;DR: This study demonstrates that inactivating mutations of KDM6A, which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2 and small-molecule inhibitors of EZh2 were effective against KDM 6A-null bladder cancer in multiple mouse models.
197
EZH2-targeted therapies in cancer: hype or a reality
TL;DR: This review highlights the recent advances in targeting EZH2, its successes, and potential limitations, and discusses the future directions of this therapeutic subclass.
191
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