A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination.
A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination.
复制标题
共价结合的抑制剂通过 CHIP 介导的泛素化触发 EZH2 降解。
DOI：
10.15252/embj.201694058
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发表时间：
2017-05-02
期刊：
影响因子：
--
通讯作者：
Chen W
中科院分区：
文献类型：
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作者：
Wang X;Cao W;Zhang J;Yan M;Xu Q;Wu X;Wan L;Zhang Z;Zhang C;Qin X;Xiao M;Ye D;Liu Y;Han Z;Wang S;Mao L;Wei W;Chen W
zeste增强子同源物2（EZH 2）是一种重要的癌基因，是治疗恶性肿瘤的重要靶点。目前的EZH 2抑制剂在一些淋巴瘤中强烈抑制突变体EZH 2的增强的酶功能。然而，最近发现EZH 2具有PRC 2和甲基转移酶独立作用，这表明需要完全抑制EZH 2的所有致癌功能。在这里，我们报告了一种独特的EZH 2靶向策略，通过鉴定一种新的药物-这类抑制剂显著抑制H3 K27 Me 3，并有效地重新激活多梳阻遏复合物2（PRC 2）沉默的肿瘤抑制基因。此外，新型抑制剂以EZH 2依赖性方式显著抑制肿瘤生长，并且携带非GNA相互作用C668 S-EZH 2突变的肿瘤表现出对抑制剂的抗性。总之，我们的研究结果确定了抑制控制GNA介导的EZH 2破坏的信号通路是一种有前途的抗癌策略。
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.