EZH2: biology, disease, and structure-based drug discovery

Jin-zhi Tan, Yan Yan, Xiao-xi Wang, Yi Jiang, H Eric Xu
DOI: 10.1038/aps.2013.161


Jin-zhi TAN1, *, Yan YAN1, Xiao-xi WANG1, Yi JIANG1, H Eric XU1, 2, *
1VARI-SIMM Center, Center for Structure and Function of Drug Targets, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, 333 Bostwick Ave, NE, Grand Rapids, MI 49503, USA

EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is a highly conserved histone methyltransferase that methylates lysine 27 of histone 3. Overexpression of EZH2 has been found in a wide range of cancers, including those of the prostate and breast. In this review, we address the current understanding of the oncogenic role of EZH2, including its PRC2-dependent transcriptional repression and PRC2-independent gene activation. We also discuss the connections between EZH2 and other silencing enzymes, such as DNA methyltransferase and histone deacetylase. We comprehensively address the architecture of the PRC2 complex and the crucial roles of each subunit. Finally, we summarize new progress in developing EZH2 inhibitors, which could be a new epigenetic therapy for cancers.

Keywords: EZH2; PRC2; transcriptional repression; gene activation; anticancer drug; crystal structure; SET domain; methyltransferase inhibitor; epigenetic therapy

We thank David NADZIEJKA for scientific editing and critical comments. This work was supported in part by the Jay and Betty Van Andel Foundation, Amway (USA), the National Natural Science Foundation of China (NSFC 81123004), and Ministry of Science and Technology (China) grants 2012CB910403 and 2013CB910601.
* To whom correspondence should be addressed.
E-mail (Jin-zhi TAN); (H Eric XU)
Received 2013-08-14 Accepted 2013-09-28

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