LOC730101 improves ovarian cancer drug sensitivity by inhibiting autophagy-mediated DNA damage repair via BECN1

• Published in: Cell death & disease 2024-12, Vol.15 (12), p.893-16
• Main Authors: Zhong, Yancheng, Shuai, Yang, Yang, Juan, Zhang, Mojian, He, Tiantian, Zheng, Leliang, Yang, Sheng, Peng, Shuping
• Format: Article
• Language: English
• Subjects: 101/58; 13/1; 13/106; 13/109; 13/2; 13/31; 13/89; 14/32; 38/47; 631/67/1059/2326; 631/80/82/39; 64/60; 82/80; 96/2; Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Beclin-1 - genetics; Beclin-1 - metabolism; Biochemistry; Biomedical and Life Sciences; Cancer therapies; Cell Biology; Cell Culture; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cisplatin - therapeutic use; DNA damage; DNA Damage - drug effects; DNA repair; DNA Repair - drug effects; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunology; Life Sciences; Mice; Mice, Nude; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Phosphorylation; Platinum; Poly(ADP-ribose) polymerase; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Ubiquitination
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-07278-1

Drug resistance and recurrence are still the bottlenecks in the clinical treatment of ovarian cancer (OC), seriously affecting patients’ prognosis. Therefore, it is an urgent challenge for OC to be overcome towards precision therapy by studying the mechanism of OC drug resistance, finding new drug resistance targets and developing new effective treatment strategies. In this study, we found that lncRNA LOC730101 played an essential role in attenuating drug resistance in OC. LOC730101 was significantly down-regulated in platinum-resistant ovarian cancer tissues, and ectopic overexpression of LOC730101 substantially increased chemotherapy-induced apoptosis. Mechanistically, LOC730101 specifically binds to BECN1 and inhibits the formation of autophagosome BECN1/VPS34 by reducing phosphorylation of BECN1, thereby inhibiting autophagy and promoting drug sensitivity in ovarian cancer cells following treatment with cisplatin and PARP inhibitors. Moreover, LOC730101 inhibits the expression and activity of RNF168 via p62, which in turn affects H2A ubiquitination-mediated DNA damage repair and promotes drug sensitivity in ovarian cancer cells. Our findings demonstrated that LOC730101 played an important role in regulating the formation of the autophagic complex and that inhibition of autophagy significantly enhances the drug sensitivity of OC. And LOC730101 may be used as a prognostic marker to predict the sensitivity of OC to platinum and PARP inhibitors.