The MAZ-POLD1 Signaling Axis Drives Cisplatin Resistance in Bladder Cancer by Activating DNA Damage Repair

Abstract

Simple Summary Cisplatin resistance severely limits therapeutic benefits for bladder cancer patients. In this study, we first verified that POLD1 was markedly overexpressed in cisplatin-resistant BC tissues and cells. Functional assays demonstrated that POLD1 knockdown remarkably impaired DDR capacity in cisplatin-resistant BC cells and restored their chemosensitivity to cisplatin in vitro, indicating that POLD1 is a key driver of cisplatin resistance. Further mechanistic experiments revealed that POLD1 physically interacted with ATM to facilitate ATM phosphorylation, which further triggered HR repair signaling. In addition, the transcription factor MAZ directly bound to the promoter region of POLD1 to transcriptionally activate POLD1 expression. Together, the MAZ–POLD1 axis represents a key driver of cisplatin resistance in bladder cancer. Our findings suggest that targeting this pathway may offer a promising new strategy to overcome drug resistance and improve clinical outcomes for bladder cancer patients.