HNRNPA2B1 as an RNA Switch Trigger Modulate MicroRNA-Mediated Regulation of CDK6

Abstract

An RNA switch is a regulatory cis-element, and its function is dependent on RNA structure transformation, which can be triggered by specific trans-factors, other regulatory RNAs and metabolites. There are instances where the microRNA (miRNA) and the corresponding target both exist in a cell, but the target gene silencing does not occur as expected. The mechanism behind this phenomenon is worth further investigation. Our research found that both miR-506 and its target cyclin dependent kinase 6 (CDK6) were highly co-expressed in multiple lung cancer cell lines. Sequence analyses suggested that a miR-506 binding site (1648-1654) and cis-element (1785-1795) for binding by heterogeneous nuclear ribonucleoprotein A2/B1(HNRNPA2B1) are evolutionarily conserved in the 3’ untranslated region (3’UTR) of CDK6, and form a stem structure that inactivates miR-506 function. HNRNPA2B1 denatures the stem structure to release the miR-506 binding site, leading to the recruitment of the miR-506-RISC complex for CDK6 silencing. HNRNPA2B1 also recruits the RNA helicase DExH-box helicase 9 (DHX9) to the 3’UTR of its targets, enhancing the engagement of argonaute RISC catalytic component 2 (AGO2) with the 3’UTR. This result indicates that the cis-element of the 3’UTR of CDK6 where HNRNPA2B1 binds serves as an RNA switch to regulate miRNA function. Deep understanding of the molecular basis of this phenomenon may provide novel biomarker and therapeutic targets for drug development.