Ubiquitin-mediated stabilization of KDM5B drives chemoresistance via repression of dual-specificity phosphatase 4 in ovarian cancer

Despite advances in therapeutic regimens for managing cancer progression, ovarian cancer (OVC) still depends on platinum-based chemotherapy as its first-line treatment. Acquired resistance is accompanied by abnormal alterations in epigenetic regulation; however, in-depth mechanistic studies on cisplatin-resistant OVC are lacking. Herein, we show that abnormal overexpression of histone lysine demethylase 5B (KDM5B), but not KDM5A, strongly correlates with cisplatin resistance and OVC tumor progression. Genome-wide sequencing data revealed that KDM5B removes H3K4me3 from the promoter of dual-specificity phosphatase 4 (DUSP4), activating the MAPK pathway to increase cisplatin resistance. We also found that KDM5B protein stability is dynamically controlled via the ubiquitin-proteasome system (UPS), which is mediated by ubiquitin-specific protease 7 (USP7), F-box and WD repeat domain-containing 7 (FBXW7), and homeodomain-interacting protein kinase 1 (HIPK1). KDM5B and USP7 depletion effectively resensitizes OVC to cisplatin resistance, whereas DUSP4 silencing results in resistance in vitro and in vivo. Targeting KDM5B and USP7 synergistically represses tumor progression and increases sensitivity to cisplatin. Overall, we propose two new UPS-associated proteins, USP7 and FBXW7, which are responsible for abnormal KDM5B protein regulation, and suggest a novel mechanism to overcome cisplatin resistance in OVC by targeting the KDM5B-DUSP4 axis.