Title | Analyses of the transcriptome and metabolome demonstrate that HIF1α mediates altered tumor metabolism in clear cell renal cell carcinoma. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Minton DR, Fu L, Chen Q, Robinson BD, Gross SS, Nanus DM, Gudas LJ |
Journal | PLoS One |
Volume | 10 |
Issue | 4 |
Pagination | e0120649 |
Date Published | 2015 |
ISSN | 1932-6203 |
Keywords | Aerobiosis, Animals, Carcinogenesis, Carcinoma, Renal Cell, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glycolysis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney, Kidney Neoplasms, Lactic Acid, Male, Metabolomics, Mice, Mice, Transgenic, RNA, Messenger |
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. |
DOI | 10.1371/journal.pone.0120649 |
Alternate Journal | PLoS ONE |
PubMed ID | 25830305 |
PubMed Central ID | PMC4382166 |
Grant List | P01 HD067244 / HD / NICHD NIH HHS / United States R37 HL087062 / HL / NHLBI NIH HHS / United States T32 CA062948 / CA / NCI NIH HHS / United States 5T32CA062948 / CA / NCI NIH HHS / United States |