TRIM4 modulates the ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitor in ovarian cancer  

作　　者：Xiaoxia Che Xin Guan Yiyin Ruan Lifei Shen Yuhong Shen Hua Liu Chongying Zhu Tianyu Zhou Yiwei Wang Weiwei Feng 

机构地区：[1]Department of Gynecology and Obstetrics,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China

出　　处：《Frontiers of Medicine》2025年第1期121-133,共13页医学前沿(英文版)

基　　金：funded by the National Natural Science Foundation of China(Nos.82172601 and 82303640).

摘　　要：Ovarian cancer is the most lethal malignancy affecting the female reproductive system.Pharmacological inhibitors targeting CDK4/6 have demonstrated promising efficacy across various cancer types.However,their clinical benefits in ovarian cancer patients fall short of expectations,with only a subset of patients experiencing these advantageous effects.This study aims to provide further clinical and biological evidence for antineoplastic effects of a CDK4/6 inhibitor(TQB4616)in ovarian cancer and explore underlying mechanisms involved.Patient-derived ovarian cancer organoid models were established to evaluate the effectiveness of TQB3616.Potential key genes related to TQB3616 sensitivity were identified through RNA-seq analysis,and TRIM4 was selected as a candidate gene for further investigation.Subsequently,co-immunoprecipitation and GST pull-down assays confirmed that TRIM4 binds to hnRNPDL and promotes its ubiquitination through RING and B-box domains.RIP assay demonstrated that hnRNPDL binded to CDKN2C isoform 2 and suppressed its expression by alternative splicing.Finally,in vivo studies confirmed that the addition of siTRIM4 significantly improved the effectiveness of TQB3616.Overall,our findings suggest that TRIM4 modulates ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitors in ovarian cancer treatment.TRIM4 may serve as a valuable biomarker for predicting sensitivity to CDK4/6 inhibitors in ovarian cancer.

关 键 词：TRIM4 CDK4/6 inhibitor hnRNPDL ovarian cancer 

分 类 号：R73[医药卫生—肿瘤]