Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy, with prognosis limited by extensive resistance to platinum-based therapy. Although the pregnane X receptor (PXR) has been implicated in chemoresistance, the upstream drivers of its aberrant activation in resistant EOC remain unclear. Here, we integrated bioinformatics, clinical specimen analysis, and functional assays to clarify the role of PXR in malignant progression and cisplatin resistance. PXR is significantly overexpressed in ovarian cancer, particularly in cisplatin-resistant cases, and is associated with poor overall survival. In clinical tissues, PXR and its downstream efflux transporter, MDR1, are co-regulated, with their levels correlating with advanced disease and chemoresistance. We show that DNA hypomethylation in the PXR gene promoter region is a key upstream epigenetic event driving its aberrant activation. In cisplatin-resistant tumor tissues and cell lines (A2780/DDP), the PXR promoter is significantly hypomethylated, and methylation levels are inversely correlated with PXR expression. Further studies revealed that siRNA-mediated knockdown of PXR inhibited EOC cell migration, invasion, and proliferation and restored cisplatin sensitivity, accompanied by MDR1 downregulation. Together, these results define a novel epigenetic–transcriptional pathway—PXR promoter hypomethylation leading to PXR activation and subsequent MDR1 induction—that drives EOC progression and chemoresistance. This work broadens our understanding of PXR regulation, highlighting its upstream epigenetic control, and provides a rationale for considering PXR and its epigenetic status as prognostic biomarkers as well as potential therapeutic targets to overcome drug resistance.
Wang et al. (Sat,) studied this question.