Analyses Of The Transcriptome And Metabolome To Elucidate The Role Of Hif1 Alpha In Clear Cell Renal Cell Carcinoma Metabolism.

493 Background: Clear cell renal cell carcinoma (ccRCC) is characterized by altered metabolism, including a shift from oxidative phosphorylation to glycolysis and lactate production (the Warburg effect). Here we evaluate human ccRCC tissue samples and kidney samples from the TRACK transgenic mouse model of ccRCC (that express constitutively active HIF1α in proximal tubule cells) [1] to characterize the effect of HIF1α on the renal cancer metabolome. Methods: We performed untargeted metabolomics analyses of 12 primary human ccRCCs and 10 TRACK kidney samples. In addition, we analyzed human ccRCC mRNA expression (Oncomine database) and performed RNA sequencing (RNAseq) on six TRACK kidney samples for expression of HIF1α target genes that regulate metabolism. Results: Analysis of RNA expression of HIF1α target genes in human ccRCCs and TRACK kidneys identified significantly increased transcript levels of genes responsible for mediating glucose uptake and glycolysis and suppressing the activity of the TCA cycle and mitochondrial respiration, including glucose transporter 1 (SLC2A1), glycolytic enzyme phosphofructokinase (PFKP), TCA cycle inhibitor pyruvate dehydrogenase kinase (PDK1), oxidative phosphorylation inhibitor NADH dehydrogenase 1 alpha subcomplex, 4-like 2 (NDUFA4L2), and lactate transporter (SLC16A3). Metabolomics analysis similarly demonstrated a significant increase in glycolytic intermediates and lactate, in association with a decrease in metabolites of the TCA cycle. Conclusions: These studies show that in both human ccRCC and TRACK mice HIF1α mediates a metabolic switch to aerobic glycolysis, implicating HIF1α in RCC tumorigenesis. Additionally, these data suggest that targeting the metabolic pathway (or inhibition of HIF1α) is a novel approach to treat ccRCCs.