The Functional Role Of Non-coding RNA In Tumor Metabolism And Cell Apoptosis

Retinoic acid (RA) has been used as a chemopreventive agent for breast cancer. It has been shown that HOXA5is a critical mediator of RA-induced cell growth inhibition. However, the molecular mechanisms underlying RA-induced HOXA5expression remain largely unknown. Here we report that in addition to transcriptional regulation, post-transcriptional regulation also contributes to RA-induced HOXA5expression. miR-130a, a c-Myc responsive miRNA, represses HOXA5cellular 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 HOXA5translation is dependent on the RNA-binding protein Human antigen R (HuR), which binds to3’UTR of HOXA5mRNA and increases its stability in response to RA treatment. Collectively, these results demonstrate that HuR and miR-130a dynamically regulate HOXA5gene expression via modulating HOXA5mRNA turnover and translation, respectively, thereby contributing to RA-induced growth inhibition. Hypoxia has long been linked to the Warburg effect, yet the underlying mechanism remains largely unclear. It is also not known if long non-coding RNAs (incRNAs) are involved in the contribution of hypoxia to the Warburg effect. Here we show that lincRNA-p21is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis. Hypoxia/HIF-1α-induced lincRNA-p21is able to bind HIF-1α and VHL and thus disrupts the VHL-HIF-1α interaction. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These data indicate the existence of a unique positive feedback loop between HIF-1α and lincRNA-p21that promotes glycolysis under hypoxia. The ability of lincRNA-p21to promote tumor growth is validated in mouse xerograph models. Together, these findings suggest that lincRNA-p21is an important player in the regulation of the Warburg effect, and also implicate lincRNA-p21as a valuable therapeutic target for cancer.