Targeting USP49 and ATAD5 Inhibits Cisplatin Resistance by Impairing DNA Damage Repair in Ovarian Cancer

ABSTRACT USP49 regulates various cellular processes as a deubiquitinase during the development of cancer. However, the roles of USP49 in ovarian cancer (OC) remain obscure. Here, it is shown that USP49 is amplified in OC, which is associated with elevated mRNA expression. Although USP49 inhibition has no significant influence on the proliferation of OC cells, USP49 overexpression promotes drug resistance to cisplatin treatment in Tp53‐WT OC cells. Mechanistically, USP49 decreases ubiquitination of γH2AX and enhances DNA damage repair, impairing cell apoptosis of OC cells in response to cisplatin treatment. In addition, co‐expression of USP49 and ATAD5 is identified in OC, and inhibition of USP49 and ATAD5 increases drug sensitivity to cisplatin in Tp53‐WT OC cells. In conclusion, these findings demonstrate the role of USP49 on cisplatin resistance and suggest that repressing USP49 and ATAD5 can be a potential therapeutic strategy for cisplatin‐resistant ovarian cancer.