Journal
EMBO JOURNAL
Volume 36, Issue 9, Pages 1243-1260Publisher
WILEY
DOI: 10.15252/embj.201694058
Keywords
CHIP; covalent inhibitor; EZH2; oncoprotein; ubiquitination
Categories
Funding
- National Key Research and Development Program [2016YFC0902700]
- National Natural Science Foundation of China [81572646, 81472515, 91229103]
- Shanghai Science and Technology Commission [S30206, 09431902200, 15DZ2292300, 16431903300]
- NIH grant [GM089763]
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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.
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