Unveiling the New Trick for Epigenetic Drug: Radiation Enhancement of Prostate Cancer by the EZH2 Inhibitor Tazemetostat

ABSTRACT

The enhancer of zeste homologue 2 inhibitor (EZH2i) Tazemetostat (EPZ‐6438) has demonstrated antitumour efficacy in various malignancies. This study aims to evaluate its radiosensitising potential and underlying mechanisms in prostate cancer (PCa). In vitro functional assays, including wound healing, Transwell invasion, EdU proliferation, flow cytometry, and Western blotting, were employed to assess invasion, migration, proliferation, and apoptosis. DNA damage was evaluated via comet assay, immunofluorescence staining of γH2AX/53BP1 foci, and Western blot. In vivo effects on tumour progression and survival were examined in mouse models using immunohistochemistry and TUNEL apoptosis assays. Safety was also systematically evaluated. The combination of Tazemetostat and irradiation significantly suppressed PCa cell invasion, migration, and proliferation, and promoted apoptosis compared to radiation alone. In vivo, the combination group showed inhibited tumour growth, reduced invasion, induced apoptosis, and extended survival. Mechanistically, EZH2 inhibition enhanced radiation‐induced DNA damage, increased double‐strand breaks (DSBs), and impaired DSB repair capacity. The combination therapy exhibited a favourable safety profile without observable systemic toxicity. Tazemetostat effectively enhances radiosensitivity in PCa models by augmenting DNA damage and compromising repair mechanisms. These results support the clinical translation of EZH2 inhibition as a novel radiosensitising strategy for PCa patients.