A Hypoxia-Induced Positive Feedback Loop Promotes Hypoxia-Inducible Factor 1α Stability through miR-210 Suppression of Glycerol-3-Phosphate Dehydrogenase 1-Like

Oxygen-dependent regulation of the transcription factor HIF-1 alpha relies on a family of prolyl hydroxylases (PHDs) that hydroxylate hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein at two prolines during normal oxygen conditions, resulting in degradation by the proteasome. During low-oxygen conditions, these prolines are no longer hydroxylated and HIF-1 alpha degradation is blocked. Hypoxia-induced miRNA-210 (miR-210) is a direct transcriptional target of HIF-1 alpha, but its complete role and targets during hypoxia are not well understood. Here, we identify the enzyme glycerol-3-phosphate dehydrogenase 1-like (GPD1L) as a novel regulator of HIF-1 alpha stability and a direct target of miR-210. Expression of miR-210 results in stabilization of HIF-1 alpha due to decreased levels of GPD1L resulting in an increase in HIF-1 alpha target genes. Altering GPD1L levels by overexpression or knockdown results in a decrease or increase in HIF-1 alpha stability, respectively. GPD1L-mediated decreases in HIF-1 alpha stability can be reversed by pharmacological inhibition of the proteasome or PHD activity. When rescued from degradation by proteasome inhibition, elevated amounts of GPD1L cause hyperhydroxylation of HIF-1 alpha, suggesting increases in PHD activity. Importantly, expression of GPD1L attenuates the hypoxic response, preventing complete HIF-1 alpha induction. We propose a model in which hypoxia-induced miR-210 represses GPD1L, contributing to suppression of PHD activity, and increases of HIF-1 alpha protein levels.