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A covalently bound inhibitor triggers EZH 2 degradation through CHIP ‐mediated ubiquitination

2017; Springer Nature; Volume: 36; Issue: 9 Linguagem: Inglês

10.15252/embj.201694058

1460-2075

Xu Wang, Wei Cao, Jianjun Zhang, Ming Yan, Qin Xu, Xiangbing Wu, Lixin Wan, Zhiyuan Zhang, Chenping Zhang, Xing Qin, Meng Xiao, Dongxia Ye, Yuyang Liu, Ze‐Guang Han, Shaomeng Wang, Li Mao, Wenyi Wei, Wantao Chen,

Histone Deacetylase Inhibitors Research

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