Retinoic Acid-induced HOXA5 Expression is Co-regulated by HuR and MiR-130a

Retinoic acid (RA) has been used as a chemopreventive agent for breast cancer. It has been shown that HOXA5 is a critical mediator of RA-induced cell growth inhibition. However, the molecular mechanisms underlying RA-induced HOXA5 expression remain largely unknown. Here we report that in addition to transcriptional regulation, post-transcriptional regulation also contributes to RA-induced HOXA5 expression. miR-130a, a c-Myc responsive miRNA, represses HOXA5 cellular levels under unstressed condition. Upon RA treatment, c-Myc is quickly degraded via the proteasome-dependent pathway. This in turn decreases miR-130a levels and de-represses the translation of HOXA5. We also show that the de-repression of HOXA5 translation is dependent on the RNA-binding protein Human antigen R (HuR), which binds to 3'UTR of HOXA5 mRNA and increases its stability in response to RA treatment. Collectively, these results demonstrate that HuR and miR-130a dynamically regulate HOXA5 gene expression via modulating HOXA5 mRNA turnover and translation, respectively, thereby contributing to RA-induced growth inhibition.