Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling.

Abstract

The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/β-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays <i>in vitro</i>, and by intraperitoneal tumor model <i>in vivo</i>. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/β-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both <i>in vitro</i> and <i>in vivo</i>. RBMS3 inhibited β-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/β-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.