SETD2 and EZH2: Two epigenetic drivers of prostate cancer.

Prostate cancer is a prevalent malignancy among men, characterized by complex mechanisms underlying metastasis and treatment resistance. Epigenetic modifications play a crucial role in regulating prostate cancer progression, particularly involving histone methyltransferases such as SET-domain containing 2 (SETD2) and Enhancer of Zeste homolog 2 (EZH2). SETD2 contributes to chromatin stability by catalyzing the trimethylation of histone H3 lysine 36 (H3K36me3), and its downregulation is strongly correlated with increased invasiveness and epithelial-mesenchymal transition in prostate cancer. Conversely, EZH2, the catalytic subunit of Polycomb Repressive Complex 2, mediates gene silencing through H3K27me3 modification and is frequently overexpressed in advanced disease, promoting tumor metastasis and resistance to therapy. Notably, SETD2 regulates EZH2 stability through direct protein interactions, highlighting a coordinated epigenetic regulatory axis. Multi-omics studies have revealed that SETD2 loss induces aberrant DNA methylation and activates oncogenic signaling pathways, whereas EZH2 overexpression cooperates with PI3K-AKT pathway dysregulation to drive castration-resistant prostate cancer. Although inhibitors targeting SETD2 (e.g., EZM0414) and EZH2 (e.g., tazemetostat) demonstrate antitumor activity in preclinical models, their clinical efficacy remains constrained by drug resistance and tumor microenvironment heterogeneity. Emerging evidence suggests that combining epigenetic therapies with immunotherapy may enhance therapeutic outcomes. This review comprehensively systematically examines the molecular mechanisms underlying the SETD2/EZH2 axis in prostate cancer, providing a theoretical foundation for developing precision therapies based on SETD2- or EZH2-mediated epigenetic modifications.