Epigenetic and Non-Epigenetic Functions of EZH2 in Tumor Development: Structural Basis, Signaling Network, and Targeted Intervention Strategies.

Abstract

Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that catalyzes the methylation of histone H3 lysine 27, a modification frequently dysregulated in various cancers. EZH2 plays critical roles in cell proliferation, differentiation, and gene silencing, and its abnormal overexpression is closely associated with tumor aggressiveness and poor prognosis. Inhibiting EZH2 can reactivate tumor suppressor genes and thereby suppress cancer cell growth and metastasis. Although several EZH2 inhibitors, including small molecules and nucleic acid drugs, have been developed and some have entered clinical trials, their specificity and potency still require further optimization. Tazemetostat is the first FDA-approved EZH2 inhibitor for relapsed or refractory follicular lymphoma, while other agents such as EPZ-6438 and GSK126 show promising preclinical antitumor activity. This review summarizes the association between EZH2 and tumors, and the mechanisms and pharmacological properties of EZH2 inhibitors. Future research directions and challenges are also discussed to facilitate the development of EZH2-targeted anticancer therapies strategies.