Survivin Expression is Differentially Regulated by a Selective Crosstalk between Rbm38 and miRNAs let-7b or miR-203a

Abstract

RNA-binding motif 38 (Rbm38) is a member of a protein family with a highly conserved RNA-binding motif and has been shown to regulate mRNA processing, stability, and translation. Survivin is an essential modulator of apoptotic and non-apoptotic cell death as well as a stress responder. Survivin mRNA is the fourth most frequently overexpressed transcript in the human cancer transcriptome, and its aberrant expression is associated with chemo-/radioresistance and poor prognosis. In this study, we examined whether survivin expression is regulated by Rbm38. Rbm38 bound to survivin 3′-UTR and suppressed miRNA let-7b from binding to and degrading survivin mRNA, leading to increased survivin expression. Rbm38 interacted with argonaute-2 (Ago2) and facilitated miR-203a-mediated degradation of survivin mRNA, leading to decreased survivin expression. Due to the abundance of let-7b over miR-203a, Rbm38 ultimately increased survivin expression in HCT116 and MCF7 cells. Additionally, Ser-195 in Rbm38 interacted with Glu-73/-76 in Ago2, and that Pep8, an 8 amino acid peptide spanning the region of Ser-195 in Rbm38, blocked the Rbm38-Ago2 interaction and inhibited miR-203a-mediated mRNA degradation, leading to enhanced survivin expression. Furthermore, Pep8 cooperated with YM155, an inhibitor of survivin, to suppress tumor spheroid growth and viability. Pep8 sensitized tumor cells to YM155-induced DNA damage in an Rbm38-dependent manner. Together, our data indicate that Rbm38 is a dual regulator of survivin and that Pep8/YM155 may be therapeutically explored for tumor suppression.