EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis

Jun Wang, Xufen Yu, Weida Gong, Xijuan Liu, Kwang Su Park, Anqi Ma, Yi Hsuan Tsai, Yudao Shen, Takashi Onikubo, Wen Chieh Pi, David F. Allison, Jing Liu, Wei Yi Chen, Ling Cai, Robert G. Roeder, Jian Jin, Gang Greg Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Both canonical (EZH2–PRC2) and noncanonical (EZH2-TAD–cMyc–coactivators) activities of EZH2 promote oncogenesis, which explains the slow and ineffective antitumour effect of inhibitors of the catalytic function of EZH2. To suppress the multifaceted activities of EZH2, we used proteolysis-targeting chimera (PROTAC) to develop a degrader, MS177, which achieved effective, on-target depletion of EZH2 and interacting partners (that is, both canonical EZH2–PRC2 and noncanonical EZH2–cMyc complexes). Compared with inhibitors of the enzymatic function of EZH2, MS177 is fast-acting and more potent in suppressing cancer growth. This study reveals noncanonical oncogenic roles of EZH2, reports a PROTAC for targeting the multifaceted tumorigenic functions of EZH2 and presents an attractive strategy for treating EZH2-dependent cancers.

Original languageEnglish
Pages (from-to)384-399
Number of pages16
JournalNature Cell Biology
Volume24
Issue number3
DOIs
StatePublished - Mar 2022

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