Novel SLCO2B1 mRNA isoform acts as a noncoding RNA and drives cancer progression through FMR1-mediated protein biosynthesis

The eukaryotic 5' untranslated region (5' UTR) canonically influences mRNA translation efficiency. However, the role of the 5' UTR structure in blocking mRNA translation and turning a coding RNA into a noncoding RNA remains undocumented. Herein, we discovered a novel mRNA isoform of the human solute carrier organic anion transporter family member 2B1 (SLCO2B1) gene, named SLCO2B1-isoformNovel (SLCO2B1-isoN), whose 5' end stem-loop abrogates its translational capacity and turns it into a noncoding RNA. The SLCO2B1-isoN noncoding isoform stabilizes fragile X messenger ribonucleoprotein 1 (FMR1) to trigger hepatocellular carcinoma (HCC) progression by facilitating de novo protein biosynthesis. Targeting SLCO2B1-isoN effectively inhibited orthotopic tumor xenograft growth in vivo. In conclusion, this study revealed a previously unrecognized noncoding isoform of SLCO2B1 mRNA with a 5' end stem-loop structure and highlighted the dual characteristics of mRNAs harboring protein-coding and noncoding isoforms, providing new insights into the richness of genetic information in protein-coding genes. Overall design: CUT&Tag was performed using antibodies against ZEB1, SETD1B, H3K9ac, H3K27me3, H3K4me3 to identify the binding sites across DNA in MHCC97H or HepG2 cells.