Статья

The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer

Liangliang RenClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, ChinaXingrong QingDepartment of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaJihong WeiDepartment of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaHaixin MoClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, ChinaYuanji LiuDepartment of Biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou, 510080, ChinaYaofeng ZhiClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, ChinaWenjie LuClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, ChinaMingzhu ZhengClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, ChinaWeijian ZhangDepartment of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaYuan ChenDepartment of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaYue‐Jiao ZhangDepartment of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaTaijin PanDepartment of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaQian ZhongDepartment of Gynecology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaRonggang LiDepartment of Pathology, Jiangmen Central Hospital, Jiangmen, 529030, ChinaXin ZhangClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, ChinaXiaohong RuanClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, China. [email protected]Ruyuan YuPrecision Medicine Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. [email protected]Jun LiClinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Jiangmen, 529030, China. [email protected]

2023en

ABI

Аннотация

Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.

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Идентификаторы

DOI: 10.1038/s41419-023-06084-5

Цитирования и источники

Цитирований: 2Использованных источников: 0

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