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Targeting EZH2 in cancer

Abstract

Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.

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Figure 1: The PRC2 complex and its function in transcriptional regulation.
Figure 2: EZH2 as a therapeutic target in cancer.

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Acknowledgements

K.H.K. was supported by an award from the National Cancer Center. C.W.M.R. was supported by US National Cancer Institute grants R01CA172152 and R01CA113794. The Garrett B. Smith Foundation, the Cure AT/RT Now foundation, The Avalanna Fund and Miles for Mary provided additional support.

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Correspondence to Charles W M Roberts.

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As a recipient of a Dana-Farber Cancer Institute-Novartis Institutes for Biomedical Research Drug Discovery Program research grant, C.W.M.R. received research funding and consulting fees from the Novartis Institutes for Biomedical Research.

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Kim, K., Roberts, C. Targeting EZH2 in cancer. Nat Med 22, 128–134 (2016). https://doi.org/10.1038/nm.4036

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