CCAR1 5' UTR as a natural miRancer of miR 1254 overrides tamoxifen resistance
MicroRNAs (miRNAs) typically bind to unstructured miRNA binding sites in target RNAs, leading to a mutual repression of expression. Here, we report that miR 1254 interacts with structured elements in cell cycle and apoptosis regulator 1 (CCAR1) 5' untranslated region (UTR) and this interaction enhances the stability of both molecules. miR 1254 can also act as a repressor when binding to unstructured sites in its targets. Interestingly, structured miR 1254 targeting sites act as both a functional RNA motif sensing unit, and an independent RNA functional unit that enhances miR 1254 expression. Artificially designed miRNA enhancers, termed "miRancers" can stabilize and enhance the activity of miRNAs of interest. We further demonstrate that CCAR1 5' UTR as a natural miRancer of endogenous miR 1254 re sensitizes tamoxifen resistant breast cancer cells to tamoxifen. Thus, our study presents a novel model of miRNA function, wherein highly structured miRancer like motif containing RNA fragments or miRancer molecules specifically interact with miRNAs, leading to reciprocal stabilization.
Cell Research