title: 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.
authors.affiliation: Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America.
authors.forename: Denise R
authors.initials: DR
authors.lastname: Minton
authors.affiliation: Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America.
authors.forename: Leiping
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.affiliation: Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Gross
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America; Weill Cornell Meyer Cancer Center, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.affiliation: Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, United States of America; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York, United States of America; Weill Cornell Meyer Cancer Center, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D000332:Aerobiosis; D000818:Animals; D063646:Carcinogenesis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019344:Lactic Acid / Q000096:biosynthesis; D008297:Male; D055432:Metabolomics; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D019344:Lactic Acid
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