The lncRNA ‘UCA1’ modulates the response to chemotherapy of ovarian cancer through direct binding to miR‐27a‐5p and control of UBE2N levels

• Published in: Molecular oncology 2021-12, Vol.15 (12), p.3659-3678
• Main Authors: Wambecke, Anaïs, Ahmad, Mohammad, Morice, Pierre‐Marie, Lambert, Bernard, Weiswald, Louis‐Bastien, Vernon, Mégane, Vigneron, Nicolas, Abeilard, Edwige, Brotin, Emilie, Figeac, Martin, Gauduchon, Pascal, Poulain, Laurent, Denoyelle, Christophe, Meryet‐Figuiere, Matthieu
• Format: Article
• Language: English
• Subjects: Apoptosis; Ascites; Bcl-2 protein; BIM protein; Cancer; Cancer therapies; Cell Line, Tumor; Cell Proliferation - genetics; ceRNA; Chemoresistance; Chemotherapy; Cisplatin; Comparative analysis; Down-regulation; Enzymes; Epigenetics; Female; Gene expression; Gene Expression Regulation, Neoplastic; Growth factors; Humans; Life Sciences; lncRNA UCA1; Malignancy; Medical prognosis; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Mimicry; miR‐27a‐5p; Molecular modelling; Non-coding RNA; Organoids; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Patients; patient‐derived organoid; Penicillin; Prognosis; Proteins; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Salts; Sodium; Ubiquitin-Conjugating Enzymes - genetics; Ubiquitin-Conjugating Enzymes - metabolism; Up-regulation
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13045

Ovarian cancer (OC) is the leading cause of death in patients with gynecologic cancers. Due to late diagnosis and resistance to chemotherapy, the 5‐year survival rate in patients with OC is below 40%. We observed that UCA1, a lncRNA previously reported to play an oncogenic role in several malignancies, is overexpressed in the chemoresistant OC cell line OAW42‐R compared to their chemotherapy‐sensitive counterpart OAW42. Additionally, UCA1 overexpression was related to poor prognosis in two independent patient cohorts. Currently, the molecular mechanisms through which UCA1 acts in OC are poorly understood. We demonstrated that downregulation of the short isoform of UCA1 sensitized OC cells to cisplatin and that UCA1 acted as competing endogenous RNA to miR‐27a‐5p. Upon UCA1 downregulation, miR‐27a‐5p downregulated its direct target UBE2N leading to the upregulation of BIM, a proapoptotic protein of the Bcl2 family. The upregulation of BIM is the event responsible for the sensitization of OC cells to cisplatin. In order to model response to therapy in patients with OC, we used several patient‐derived organoid cultures, a model faithfully mimicking patient’s response to therapy. Inhibition of UBE2N sensitized patient‐derived organoids to platinum salts. In conclusion, response to treatment in patients with OC is regulated by the UCA1/miR‐27a‐5p/UBE2N axis, where UBE2N inhibition could potentially represent a novel therapeutic strategy to counter chemoresistance in OC. UCA1 cytoplasmic short isoform is acting as a competing endogenous RNA for miR‐27a‐5p. Upon UCA1 down‐regulation, miR‐27a‐5p is no longer prevented to bind and downregulate its direct target UBE2N. UBE2N inhibition triggers BIM upregulation, which sensitizes cells and patient derived organoids to the cytotoxic action of platinum drugs.