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

作者：Wang, Xu; Cao, Wei; Zhang, Jianjun; Yan, Ming; Xu, Qin; Wu, Xiangbing; Wan, Lixin; Zhang, Zhiyuan; Zhang, Chenping; Qin, Xing; Xiao, Meng; Ye, Dongxia; Liu, Yuyang; Han, Zeguang; Wang, Shaomeng; Mao, Li; Wei, Wenyi^*; Chen, Wantao^*

来源：The EMBO Journal, 2017, 36(9): 1243-1260.

DOI：10.15252/embj.201694058

• CHIP
• covalent inhibitor
• EZH2
• oncoprotein
• 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.

• 出版日期2017-5-2
• 单位上海交通大学; 上海市口腔病防治院