2. Academic Validation
  3. A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination

A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination

  • EMBO J. 2017 May 2;36(9):1243-1260. doi: 10.15252/embj.201694058.
Xu Wang 1 2,  Wei Cao 1 2,  Jianjun Zhang 1 2,  Ming Yan 1 2,  Qin Xu 1 2,  Xiangbing Wu 1 2,  Lixin Wan 3,  Zhiyuan Zhang 1 2,  Chenping Zhang 1 2,  Xing Qin 1 2,  Meng Xiao 1 2,  Dongxia Ye 2,  Yuyang Liu 2,  Zeguang Han 4,  Shaomeng Wang 5,  Li Mao 1 6,  Wenyi Wei 7,  Wantao Chen 8 2
Affiliations

Affiliations

  • 1 Faculty of Oral and Maxillofacial Surgery, Department of Oral and Maxillofacial Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
  • 3 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 4 Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
  • 5 Comprehensive Cancer Center, Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
  • 6 Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD, USA.
  • 7 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA [email protected] [email protected].
  • 8 Faculty of Oral and Maxillofacial Surgery, Department of Oral and Maxillofacial Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [email protected] [email protected].
PMID: 28320739 DOI: 10.15252/embj.201694058
Abstract

Enhancer of zeste homolog 2 (EZH2) has been characterized as a critical oncogene and a promising drug target in human malignant tumors. The current EZH2 inhibitors strongly suppress the enhanced enzymatic function of mutant EZH2 in some lymphomas. However, the recent identification of a PRC2- and methyltransferase-independent role of EZH2 indicates that a complete suppression of all oncogenic functions of EZH2 is needed. Here, we report a unique EZH2-targeting strategy by identifying a gambogenic acid (GNA) derivative as a novel agent that specifically and covalently bound to Cys668 within the EZH2-SET domain, triggering EZH2 degradation through COOH terminus of Hsp70-interacting protein (CHIP)-mediated ubiquitination. This class of inhibitors significantly suppressed H3K27Me3 and effectively reactivated polycomb repressor complex 2 (PRC2)-silenced tumor suppressor genes. Moreover, the novel inhibitors significantly suppressed tumor growth in an EZH2-dependent manner, and tumors bearing a non-GNA-interacting C668S-EZH2 mutation exhibited resistance to the inhibitors. Together, our results identify the inhibition of the signaling pathway that governs GNA-mediated destruction of EZH2 as a promising anti-cancer strategy.

Keywords

CHIP; EZH2; covalent inhibitor; oncoprotein; ubiquitination.

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