Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma
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 mo...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Online |
| Language: | English |
| Published: |
Public Library of Science
2015
|
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382166/ |
| id |
pubmed-4382166 |
|---|---|
| recordtype |
oai_dc |
| spelling |
pubmed-43821662015-04-09 Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma Minton, Denise R. Fu, Leiping Chen, Qiuying Robinson, Brian D. Gross, Steven S. Nanus, David M. Gudas, Lorraine J. Research Article 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. Public Library of Science 2015-04-01 /pmc/articles/PMC4382166/ /pubmed/25830305 http://dx.doi.org/10.1371/journal.pone.0120649 Text en © 2015 Minton et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Minton, Denise R. Fu, Leiping Chen, Qiuying Robinson, Brian D. Gross, Steven S. Nanus, David M. Gudas, Lorraine J. |
| spellingShingle |
Minton, Denise R. Fu, Leiping Chen, Qiuying Robinson, Brian D. Gross, Steven S. Nanus, David M. Gudas, Lorraine J. Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma |
| author_facet |
Minton, Denise R. Fu, Leiping Chen, Qiuying Robinson, Brian D. Gross, Steven S. Nanus, David M. Gudas, Lorraine J. |
| author_sort |
Minton, Denise R. |
| title |
Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma |
| title_short |
Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma |
| title_full |
Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma |
| title_fullStr |
Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed |
Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma |
| title_sort |
analyses of the transcriptome and metabolome demonstrate that hif1α mediates altered tumor metabolism in clear cell renal cell carcinoma |
| description |
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. |
| publisher |
Public Library of Science |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382166/ |
| _version_ |
1613206483183337472 |