2. Academic Validation
  3. EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis

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

  • Nat Cell Biol. 2022 Mar;24(3):384-399. doi: 10.1038/s41556-022-00850-x.
Jun Wang # 1 2,  Xufen Yu # 3,  Weida Gong 1,  Xijuan Liu 1,  Kwang-Su Park 3,  Anqi Ma 3,  Yi-Hsuan Tsai 1,  Yudao Shen 3,  Takashi Onikubo 4,  Wen-Chieh Pi 5,  David F Allison 1 2,  Jing Liu 3,  Wei-Yi Chen 5,  Ling Cai 1 6,  Robert G Roeder 4,  Jian Jin 7,  Gang Greg Wang 8 9 10
Affiliations

Affiliations

  • 1 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 3 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, USA.
  • 5 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • 6 Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • 7 Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 8 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. [email protected].
  • 9 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. [email protected].
  • 10 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. [email protected].
  • # Contributed equally.
PMID: 35210568 DOI: 10.1038/s41556-022-00850-x
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.

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