Analyses of the transcriptome and metabolome demonstrate that HIF1α mediates altered tumor metabolism in clear cell renal cell carcinoma.

Abstract

Hypoxia inducible factor 1 alpha (HIF1α) is a transcription factor that is frequently stabilized and active in human clear cell renal cell carcinoma (ccRCC). We have found that constitutively active HIF1α is sufficient to cause neoplastic transformation in a murine model of ccRCC termed the TRACK model. RNA sequencing (RNAseq) and untargeted metabolomics analyses of samples from TRACK kidneys demonstrate that HIF1α activates the transcription of genes that cause increased glucose uptake, glycolysis, and lactate production, as well as a decrease in the flux of pyruvate entering the tricarboxylic acid (TCA) cycle and a decrease in oxidative phosphorylation; these changes are identical to those observed in human ccRCC samples. These studies show that a constitutively active HIF1α promotes tumorigenesis in TRACK mice by mediating a metabolic switch to aerobic glycolysis, i.e., the Warburg effect, and suggest that TRACK mice are a valid model to test novel therapies targeting metabolic changes to inhibit human ccRCC.