A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination.
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.
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Xu
X
Wang
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Wei
W
Cao
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Jianjun
J
Zhang
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Ming
M
Yan
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Qin
Q
Xu
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Xiangbing
X
Wu
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Lixin
L
Wan
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Zhiyuan
Z
Zhang
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Chenping
C
Zhang
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Xing
X
Qin
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.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Meng
M
Xiao
Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Dongxia
D
Ye
Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Yuyang
Y
Liu
Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Zeguang
Z
Han
Comprehensive Cancer Center, Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
Shaomeng
S
Wang
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.|Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, Baltimore, MD, USA.
Li
L
Mao
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA wwei2@bidmc.harvard.edu chenwantao196323@sjtu.edu.cn.
Wenyi
W
Wei
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 wwei2@bidmc.harvard.edu chenwantao196323@sjtu.edu.cn.|Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
Wantao
0000-0002-9307-162X
W
Chen
D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014966:Xanthenes / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014966:Xanthenes; C045863:neo-gambogic acid; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases

CHIP
; EZH2; covalent inhibitor; oncoprotein; ubiquitination