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

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. image Aberrant activation of PRC 2 can block expression of key tumor suppressors and contribute to oncogenesis. The discovery of a drug that triggers specific degradation of PRC 2 component EZH 2 offers a new therapeutic strategy for cancer treatment. Derivatives of gambogenic acid ( GNA ) represent a new and unique category of EZH 2 inhibitors. GNA ‐derivatives bind covalently to EZH 2, but not other methyltransferases, and trigger its degradation. The E3 ubiquitin ligase CHIP governs ubiquitination and destruction of EZH 2 oncoprotein upon covalent binding of GNA derivatives. GNA derivatives efficiently inhibit cancer growth in vivo while showing little toxic side effect.