TIP60 mediates chemoresistance by reducing cisplatin-DNA adduct formation and enhancing their repair

Cisplatin is a frontline chemotherapeutic agent for squamous cell carcinoma (SCC), yet resistance remains a major obstacle to effective treatment. Our previous work demonstrated that genetic knockdown or pharmacological inhibition of TIP60 sensitizes cisplatin-resistant SCC cells, induces cell cycle arrest and promotes cell death, suggesting a central role for TIP60 in mediating platinum resistance. Here, we demonstrate that TIP60 promotes cisplatin resistance by upregulating drug efflux transporter, suppressing intracellular drug accumulation, and enhancing DNA damage repair. Using both intrinsic and acquired cisplatin-resistant SCC cell line models, we show that elevated TIP60 levels correlate with reduced cisplatin-DNA adduct formation, accelerated repair kinetics, and increased cell survival. Mechanistically, we demonstrate that TIP60 plays a significant role in facilitating resistance to cisplatin through two key pathways. First, it increases the expression of ABCC1, which enhances the efflux of cisplatin and decreases its intracellular accumulation. Second, TIP60 promotes the expression of XPC, an essential element of the nucleotide excision repair (NER) pathway, facilitating the repair of DNA adducts. We show that TIP60 depletion decreases ABCC1 expression and increases cisplatin-DNA adduct accumulation, an effect also observed with the ABCC1 inhibitor, MK-571. Similarly, TIP60 knockdown impairs DNA repair and downregulates DNA damage response (DDR) genes, including XPC. Combining TIP60 inhibition with either ABCC1 inhibitor, MK-571 or spironolactone, which blocks NER further decreases cell survival and increases cell death. Together, these findings reveal a dual role for TIP60 in promoting cisplatin resistance through the coordinated regulation of drug efflux and DNA repair highlighting its potential as a therapeutic target to overcome platinum resistance in SCC.