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

Abstract

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.

Keywords

TRIM4 / CDK4/6 inhibitor / hnRNPDL / ovarian cancer

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Acknowledgements

We thank AJE for its linguistic assistance during the preparation of this manuscript. This study was funded by the National Natural Science Foundation of China (Nos. 82172601 and 82303640).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1103-5 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Xiaoxia Che, Xin Guan, Yiyin Ruan, Lifei Shen, Yuhong Shen, Hua Liu, Chongying Zhu, Tianyu Zhou, Yiwei Wang, and Weiwei Feng declare no conflicts of interest.

This study was approved by the Committees for Ethical Review of Research involving Human Subjects at Shanghai Jiao Tong University School of Medicine. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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