ArticleThe EMBO journal2017
A covalently bound inhibitor triggers EZH2 degradation through CHIP-mediated ubiquitination.
Article in The EMBO journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed.
- Structural characteristics and SARs of EZH2 inhibitors.Molecular diversity · 2026Review
- Natural modulators of enhancer of zeste homolog 2 (EZH2): potential epigenetic regulators of aging-associated pathways.Biogerontology · 2026Review
- Monovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3.Nature chemistry · 2026Article
- Gambogenic acid ameliorates inflammation by inhibiting HK1-mediated Warburg effect and NLRP3 inflammasome activation in sepsis.Acta pharmaceutica Sinica. B · 2026Article
- Article
- Genetic depletion or pharmacological degradation of EZH2 attenuates renal fibrosis via suppressing Notch signaling.Clinical epigenetics · 2025Article
- The YYR (YY1- RKIP) Regulatory Axis in the pathogenesis of Cancer and Immune Evasion.Journal of experimental & clinical cancer research : CR · 2025Review
- Structure-guided design and development of cyclic peptide allosteric activators of Polycomb Repressive Complex 2.bioRxiv : the preprint server for biology · 2025Article
- S-nitrosylation of EZH2 alters PRC2 assembly, methyltransferase activity, and EZH2 stability to maintain endothelial homeostasis.Nature communications · 2025Article
- Cancer epigenetic therapy: recent advances, challenges, and emerging opportunities.Epigenomics · 2025Review
- Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.Therapeutic advances in medical oncology · 2025Review
- Targeting EZH2 in Cancer: Mechanisms, Pathways, and Therapeutic Potential.Molecules (Basel, Switzerland) · 2024Review
- The role of deubiquitinase USP2 in driving bladder cancer progression by stabilizing EZH2 to epigenetically silence SOX1 expression.Translational oncology · 2024Article
- Pharmacological inhibition of EZH2 using a covalent inhibitor suppresses human ovarian cancer cell migration and invasion.Molecular and cellular biochemistry · 2024Article
- Induced protein degradation for therapeutics: past, present, and future.The Journal of clinical investigation · 2024Review
- EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma.Clinical epigenetics · 2023Article
- Yin Yang 1-Induced Long Noncoding RNA DUXAP9 Drives the Progression of Oral Squamous Cell Carcinoma by Blocking CDK1-Mediated EZH2 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- The roles of EZH2 in cancer and its inhibitors.Medical oncology (Northwood, London, England) · 2023Review
- Discovery of IHMT-337 as a potent irreversible EZH2 inhibitor targeting CDK4 transcription for malignancies.Signal transduction and targeted therapy · 2023Article
- Exploring the therapeutic potential of targeting polycomb repressive complex 2 in lung cancer.Frontiers in oncology · 2023Review
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
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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