Circular RNA circ_ARHGEF28 inhibits MST1/2 dimerization to suppress Hippo pathway to induce cisplatin resistance in ovarian cancer

Background: The chemotherapy drug cisplatin is the backbone of the treatment of ovarian cancer, and patients who develop resistance to cisplatin are associated with poor survival. Circular RNA was associated with cisplatin resistance of ovarian cancer.However,the mechanism of interaction between circular RNA and cisplatin resistance of ovarian cancer remains unclear and needs to be further explored. Methods: : High-throughput sequencing analysis was performed to identify circRNA expression profiles in cisplatin-resistant ovarian cancer. Gain and loss function experiment were performed to verify the sensitivity of cisplatin in vitro and in vivo . Fluorescence in situ hybridization was performed to demonstrate the cellular location of circRNA.RNA pulldown and RNA immunoprecipitation were were performed to identify the binding protein of circRNA. Result: We found that circ_ARHGEF28 overexpressed in some cisplatin-resistant ovarian cancer tissues and cell lines and was associated with poor PFS in ovarian cancer patients.The circ_ARHGEF28 induced cisplatin resistance in ovarian cancer in vitro and in vivo. Furthermore, circ_ARHGEF28interacted directly with MST1/2 and blocked the SARAH coiled-coil binding domains of MST1/2 to deactivate the Hippo pathway. Conclusion: We identified a novel circular RNA circ_ARHGEF28 induced cisplatin resistance in ovarian cancer by suppressing the Hippo pathway.As a result of our findings, targeting circ_ARHGEF28 may be a potential strategy to overcome cisplatin resistance in ovarian cancer.