USP7 promotes chemotherapy resistance and DNA damage response through stabilizing and deubiquitinating KDM4A in bladder cancer

Bladder cancer is a common malignancy, and the insensitivity of advanced bladder cancer to cisplatin poses an imminent challenge to treatment. Our study aims to identify novel targets that mediate cisplatin responsiveness in bladder cancer. Accordingly, overexpression of the histone demethylase KDM4A in clinical cohorts was found in association with poor prognosis. Tissue culture and animal tests showed that KDM4A pis ro-proliferative in bladder cancer cells. Using co-immunoprecipitation and mass spectrometry methods, we identified that USP7 is an interacting partners in KDM4A protein complex, in which USP7 catalyzes KDM4A proteins deubiquitination that uncouples the proteasome-dependent degradation. In accordance, a positive correlation between USP7 and KDM4A protein expression was noted in bladder cancer clinical samples. Functional validation tests confirmed that USP7 and KDM4A act complementarily to drive bladder cancer cell proliferation. Importantly, cell and animal assays all evidenced that antagonizing the USP7-KDM4A axis would aggravate cisplatin-induced DNA damage and sensitize cisplatin responsiveness.