Regulation of Glucose and Lipid Metabolism by the PHD/HIF/VHL Pathway

The frequently altered expression of metabolism genes in solid tumors such as clear cell renal cell cancer (ccRCC) has reinforced the importance of dysregulated metabolism in driving tumor expansion.  Indeed, constitutive activation of the hypoxia inducible transcription factor (HIF) through mutations in the von Hippel Lindau (VHL) tumor suppressor gene or through exposure to hypoxia, results in enhanced glucose uptake, glycolytic flux, lactate secretion and suppression of mitochondrial activity. Conversely, reactive oxygen species produced by the mitochondria stimulate HIF-dependent transcription, creating an intricate signaling loop that balances mitochondrial oxygen consumption with the cellular response to hypoxia. In addition to stimulating glycolysis while suppressing OXPHOS, hypoxia has also been demonstrated to stimulate de novo lipogenesis through reductive glutamine metabolism, although it has not yet known how this reductive glutamine metabolism contributes to lipid accumulation in solid tumors and the clear cell phenotype in ccRCC. Importantly, HIF-dependent metabolic changes have been exploited therapeutically, indicating that a more comprehensive understanding of HIF regulated metabolism may yield novel anti-cancer therapies. Oxidative metabolism, which broadly encompasses carbohydrate oxidation, glutamine oxidation, and fatty acid β-oxidation, is controlled by a number of nuclear and mitochondrial transcription factors that together promote the biogenesis and enzymatic function of mitochondria and is often found repressed in many tumors including ccRCC. Our recent studies indicate that PGC-1α is suppressed in ccRCC through a HIF-α/Dec1 transcriptional axis.  The suppression of PGC-1α in VHL-wild type renal proximal tubule cells is associated with reduced mitochondrial activity and acquisition of the clear cell (lipid and glycogen accumulation) phenotype, a histological hallmark of ccRCC.  These findings provide the first evidence linking the clear cell phenotype to multiple aspects of renal tumorigenesis and raise the potential for PGC-1α stimulation as a novel therapeutic modality in the treatment of renal cell carcinoma, and potentially other solid tumors. Our goals are to explore the molecular mechanisms governing lipid homeostasis in cancer and to characterize their contribution to tumorigenesis and identify ways that they can be therapeutically targeted. 

Selected Publications

  1.  Taniguchi, C.M., Finger, E.C., Krieg, A.J., Wu, C., Diep, A.N., LaGory, E.L., Wei, K., McGinnis, L.M. Yuan, J., Kuo, C.J. and Giaccia, A.J.  Cross-talk between hypoxia and insulin signaling via PHD3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nature Med 19:1325-1330, 2013 (PMCID: PMC4089950).
  2. Wei, K., Piecewicz, S., McGinnis, L.M., Taniguchi, C.M., Wiegand, S.J., Anderson, K., Chan, C.W., Mulligan, K.X., Kuo, D., Yuan, J., Vallon, M., Morton, L.C., Lefai, E., Simon, M.C., Maher, J.J., Annes, J.P., McGuinness, O.P., Thurston, G., Giaccia, A.J. and Kuo, C.J.  A liver HIF-2a/Irs2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition.  Nature Med 19:1331-1337, 2013 (PMCID: PMC3795838).
  3. LaGory, E.L., Wu, C., Taniguchi, C.M., Ding, C.K., Chi, J.T., von Eyben, R., Scott, D.A., Richardson, A.D. and Giaccia, A.J. Suppression of PGC-1α is critical for reprogramming oxidative metabolism in renal cell carcinoma. Cell Reports 12:116-127, 2015
  4. LaGory, E.L. and Giaccia, A.J.  The ever-expanding role of HIF in tumour and stromal biology.  Nat Cell Biol 18:356-365, 2016 (PMCID: PMC4898054).