Background/Aim: Endometrial cancer (EC) incidence is increasing globally, highlighting the need for novel therapies targeting molecular drivers of malignancy. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase implicated in tumor progression, is overexpressed in EC; however, its precise role and therapeutic potential remain unclear. In this study, we aimed to investigate EZH2 expression, its functional role, and the efficacy of EZH2 inhibitors in EC cell lines. Materials and Methods: EZH2 expression was analyzed in eight EC cell lines using western blotting and immunocytochemistry. The efficacy of five EZH2 inhibitors (CPI-1205, EI1, EPZ005687, EPZ-6438, and GSK126) was evaluated using drug sensitivity assays. Furthermore, functional analyses, including cell proliferation, colony formation, migration, and invasion assays, were performed following siRNA-mediated EZH2 knockdown in HEC-50B cells. Results: Variable EZH2 expression was observed across EC cell lines, with high levels in HEC-50B and Ishikawa 3-H-12 cells. EZH2-high expressing cell lines were markedly more sensitive to EZH2 inhibitors, particularly GSK126, compared to EZH2-low expressing lines. EZH2 knockdown in HEC-50B cells reduced EZH2 expression and decreased sensitivity to EZH2 inhibitors, confirming target specificity, while also attenuating cell proliferation, colony formation, migration, and invasion. Conclusion: EZH2 plays a crucial role in promoting malignant phenotypes in EC, and its expression level correlates with cellular sensitivity to EZH2 inhibitors. These findings suggest that EZH2 could serve as a valuable therapeutic target and predictive biomarker for personalized medicine in EC.
ONISHI et al. (2026) studied this question.