UQCRH promoter methylation limits apoptosis and drug sensitivity in ovarian cancer cells

Abstract Overcoming chemoresistance is a major challenge in ovarian cancer, where impaired apoptosis and mitochondrial dysfunction play key roles. Ubiquinol-cytochrome c reductase hinge protein (UQCRH), a component of mitochondrial complex III, is involved in intrinsic apoptosis, but its role in ovarian cancer remains unclear. We investigated UQCRH expression, regulation, and function in ovarian cancer. Pan-cancer analyses showed UQCRH downregulation across multiple malignancies, with particularly low expression in ovarian cancer. Immunohistochemistry confirmed reduced expression in clinical specimens, including complete loss in a subset of clear cell carcinomas. Functionally, UQCRH overexpression suppressed tumor growth and peritoneal dissemination in mouse models. While it did not affect proliferation or migration, it significantly enhanced apoptotic sensitivity under stress and in response to apoptotic stimuli. Mechanistically, UQCRH promoter hypermethylation was observed in ovarian cancer and inversely correlated with mRNA expression, as assessed by nanopore sequencing, indicating epigenetic silencing. Treatment with a DNA demethylating agent restored UQCRH expression and enhanced cisplatin-induced apoptosis. These findings suggest that epigenetic suppression of UQCRH may contribute to apoptotic resistance and chemoresistance. UQCRH may represent a potential biomarker for epigenetic priming therapy, particularly in clear cell ovarian cancer.