Epigenetic regulation of cancer progression by EZH2: from biological insights to therapeutic potential.
TLDR
The molecular functions of EZH2 are discussed, recent findings regarding the physiological functions and related regulation of E zeste homolog 2 in cancer pathogenesis are highlighted, and the emerging roles of EzH2 in tumor immunity are summarized.Abstract:
Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a catalytic component of PRC2, catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. EZH2 also functions both as a transcriptional suppressor and a transcriptional co-activator, depending on H3K27me3 or not and on the different cellular contexts. Unsurprisingly, numerous studies have highlighted the role of EZH2 in cancer development and progression. Through modulating critical gene expression, EZH2 promotes cell survival, proliferation, epithelial to mesenchymal, invasion, and drug resistance of cancer cells. The tumor suppressive effects of EZH2 are also identified. What is more, EZH2 has decisive roles in immune cells (for example, T cells, NK cells, dendritic cells and macrophages), which are essential components in tumor microenvironment. In this review, we aim to discuss the molecular functions of EZH2, highlight recent findings regarding the physiological functions and related regulation of EZH2 in cancer pathogenesis. Furthermore, we summarized and updated the emerging roles of EZH2 in tumor immunity, and current pre-clinical and clinical trials of EZH2 inhibitors in cancer therapy.read more
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Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy
Abdullah Al Emran,Aniruddha Chatterjee,Euan J. Rodger,Jessamy Tiffen,Stuart J. Gallagher,Michael R. Eccles,Peter Hersey +6 more
TL;DR: An updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes is presented.
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Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader
Frances Potjewyd,Anne-Marie W. Turner,Joshua Beri,Justin M. Rectenwald,Jacqueline Norris-Drouin,Stephanie H. Cholensky,David M. Margolis,Kenneth H. Pearce,Laura E. Herring,Lindsey I. James +9 more
TL;DR: A chemical degrader (UNC6852) that targets polycomb repressive complex 2 (PRC2) and degrades both wild-type and mutant EZH2, and additionally displays anti-proliferative effects in this cancer model system.
References
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Journal ArticleDOI
The Polycomb complex PRC2 and its mark in life
Raphaël Margueron,Danny Reinberg +1 more
TL;DR: This work has uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes, and expanded the perspectives on its function and regulation.
Journal ArticleDOI
The polycomb group protein EZH2 is involved in progression of prostate cancer
Sooryanarayana Varambally,Saravana M. Dhanasekaran,Ming Zhou,Terrence R. Barrette,Chandan Kumar-Sinha,Martin G. Sanda,Debashis Ghosh,Kenneth J. Pienta,Richard George Antonius Bernardus Sewalt,Arie P. Otte,Mark A. Rubin,Arul M. Chinnaiyan +11 more
TL;DR: Dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
Journal ArticleDOI
Histone methylation: a dynamic mark in health, disease and inheritance
Eric L. Greer,Yang Shi +1 more
TL;DR: This work provides a broad overview of how histone methylation is regulated and leads to biological outcomes and suggests its links to disease and ageing and possibly to transmission of traits across generations are illustrated.
Journal ArticleDOI
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
Michael T. McCabe,Heidi M. Ott,Gopinath Ganji,Susan Korenchuk,Christine Thompson,Glenn S. Van Aller,Yan Liu,Alan P. Graves,Anthony Della Pietra,Elsie Diaz,Louis V. LaFrance,Mellinger Mark,Celine Duquenne,Xinrong Tian,Ryan G. Kruger,Charles F. McHugh,Martin Brandt,William H. Miller,Dashyant Dhanak,Sharad K. Verma,Peter J. Tummino,Caretha L. Creasy +21 more
TL;DR: GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes and markedly inhibits the growth of EzH2 mutant DLBCL xenografts in mice are demonstrated.
Journal ArticleDOI
Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin
Ryan D. Morin,Nathalie A. Johnson,Tesa M. Severson,Andrew J. Mungall,Jianghong An,Rodrigo Goya,Paul Je,Merrill Boyle,Bruce Woolcock,Florian Kuchenbauer,Damian Yap,Humphries Rk,Obi L. Griffith,Sohrab P. Shah,Hao Zhu,Kimbara M,Shashkin P,Charlot Jf,Tcherpakov M,Richard Corbett,Angela K Y Tam,Richard Varhol,Duane E Smailus,Michelle Moksa,Yongjun Zhao,Allen Delaney,Hong Qian,Inanc Birol,Jacquie Schein,Richard A. Moore,Robert A. Holt,Douglas E. Horsman,Joseph M. Connors,Joseph M. Connors,Steven J.M. Jones,Samuel Aparicio,Martin Hirst,Randy D. Gascoyne,Marco A. Marra,Marco A. Marra +39 more
TL;DR: Recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27), are reported, consistent with the notion that EZh2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
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