SIAH1-Mediated RPS3 Ubiquitination Contributes to Chemosensitivity in Epithelial Ovarian Cancer

The E3 ligase SIAH1 is deregulated in human cancers and correlated with poor prognosis, but its contributions to chemoresistance in epithelial ovarian cancer (EOC) are not evident. Herein we show that SIAH1 is decreased in EOC tumour tissues and cell lines and negatively correlated with RPS3 level. SIAH1 overexpression suppresses tumour cell growth, colony formation, invasion, metastasis, and cisplatin resistance in vivo and in vitro. SIAH1 promoted RPS3 ubiquitination and degradation using the RING-finger domain, which was required for RPS3 localization to the cytoplasm for subsequent NF-κB inactivation, thereby conferring chemosensitivity. Moreover, ectopic expression of RPS3 or depletion of RPS3 ubiquitination mediated by SIAH1 via the K214R mutant significantly impaired cisplatin-induced tumour suppression in cells stably expressing SIAH1. Together, our findings reveal a tumour suppressor function of SIAH1 and provide evidence that the SIAH1-RPS3-NF-κB axis may act as an appealing strategy to tackle treatment resistance in EOC. Funding: This research was supported by Natural Science Foundation of China (Grant Nos.81672913 and 81871343), Social Development Project of Jiangsu (Grant Nos.BE2017698 and BE2018693), Natural Science Foundation of Jiangsu Province (Grant Nos.BK20181226 and BK20201223), Jiangsu Provincial Medical Youth Talent (Grant Nos.QNRC2016460 and FRC201788) and Nantong health and Family Planning Commission (Grant No.QA2020005) . Declaration of Interest: None to declare. Ethical Approval: All Clinical research were performed with the approval of the Jiangsu University Ethics Committee, and informed consent was obtained from all patients.