Lysine demethylase 5D promotes CHEK1 inhibitor sensitivity through p38-mediated cyclooxygenase-2 expression in castration-resistant prostate cancer cells

作者：Wenxiao Zheng, Shichen Li, Raymond E. West, Ella R. Donahue, Thomas D. Nolin, Song Li, Qiming J. Wang · 发表于：Journal of Pharmacology and Experimental Therapeutics · 年份：2025 · DOI：10.1016/j.jpet.2025.103769 · 被引用次数：1 · 研究领域：Epigenetics and DNA Methylation、Prostate Cancer Treatment and Research、DNA Repair Mechanisms

CHEK1 (CHK1) is a key regulator of the G2/M checkpoint and DNA damage response. Although CHK1 inhibitors (CHK1is) show promise in multiple clinical trials, their further advancement is hampered by the lack of reliable predictive biomarkers. Our previous study demonstrated a nearly 20-fold difference in the sensitivity to a clinical-stage CHK1i SRA737 in prostate cancer (PC) cells. Through bioinformatics analysis, an epigenetic regulator, lysine demethylase 5D (KDM5D), was identified as a potential mediator of differential responses to SRA737. Gain- or loss-of-function studies were performed to investigate how altered KDM5D expression affects CHK1i sensitivity and the underlying mechanisms. Our data demonstrated that higher KDM5D expressions correlated with greater sensitivity to CHK1is in PC cells. In patients with castration-resistant PC (CRPC), a high KDM5D score predicted a better patient response to CHK1i. Knockdown of KDM5D in SRA737-sensitive KDM5D-expressing cells caused resistance to SRA737. Correspondingly, a higher sensitivity to SRA737 was observed in a docetaxel-resistant CRPC cell line with elevated KDM5D, and silencing KDM5D caused resistance to this inhibitor. Mechanistically, depletion of KDM5D activated p38 and induced cyclooxygenase-2 (COX-2) and ATP-binding cassette transporter expression. Inhibition of p38 or COX-2 partially reversed the resistance to CHK1i induced by KDM5D knockdown. Additionally, silencing of p38 increased KDM5D protein expression, indic...