Targeting EZH2 in Cancer: From Molecular Mechanisms to Clinical Translation

Abstract

Enhancer of zeste homolog 2 (EZH2), a core histone methyltransferase in polycomb repressive complex 2 (PRC2), can regulate various downstream genes or proteins in a PRC2-dependent or PRC2-independent manner. Dysregulation of EZH2 is closely related to cancer progression and therapy resistance. However, targeting EZH2 for cancer therapy still encounters many challenges and needs further exploration. In this review, we elaborate on the biological functions and molecular mechanisms of EZH2 in cancer progression, drug resistance, and tumor microenvironment, highlighting its potential significant value as a tumor biomarker and therapeutic target. We also expound the cancer treatment strategies based on targeting EZH2 and outline the anti-cancer effects and regulatory mechanisms of selective small-molecule inhibitors, degraders and natural compounds which target EZH2 in various preclinical cancer models. In addition, we summarize the applications of EZH2 selective small-molecule inhibitors and combination therapy in clinical trials and discuss the opportunities and challenges of targeting EZH2 for cancer treatment. We aim to highlight the significance of targeting EZH2 in cancer and explore more targeted therapeutic strategies for clinical translation and cancer therapy.

Keywords

cancer / clinical translation / EZH2 / molecular mechanism / therapeutic strategy

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