HIF-1 mediates the Warburg effect in clear cell renal carcinoma

Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. O ₂-dependent hydroxylation of two proline residues in the HIF-1α subunit is necessary for the binding of the von Hippel-Lindau (VHL) protein, which is a component of a ubiquitin protein ligase that ubiquitinates HIF-1α, leading to its degradation by the proteasome. In the majority of cases of the clear cell type of renal carcinoma, both VHL genes are inactivated by mutation or epigenetic silencing, leading to dysregulated HIF-1 transcriptional activity. VHL loss-of-function leads, under aerobic conditions, to a HIF-1-dependent reprogramming of glucose and energy metabolism that includes increased glucose uptake, glycolysis, and lactate production accompanied by a reciprocal decrease in respiration. These findings delineate for the first time the molecular mechanisms underlying the Warburg effect in a human cancer.