HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity

Cancer Cell. 2007 May;11(5):407-20. doi: 10.1016/j.ccr.2007.04.001.


Many cancer cells are characterized by increased glycolysis and decreased respiration, even under aerobic conditions. The molecular mechanisms underlying this metabolic reprogramming are unclear. Here we show that hypoxia-inducible factor 1 (HIF-1) negatively regulates mitochondrial biogenesis and O(2) consumption in renal carcinoma cells lacking the von Hippel-Lindau tumor suppressor (VHL). HIF-1 mediates these effects by inhibiting C-MYC activity via two mechanisms. First, HIF-1 binds to and activates transcription of the MXI1 gene, which encodes a repressor of C-MYC transcriptional activity. Second, HIF-1 promotes MXI-1-independent, proteasome-dependent degradation of C-MYC. We demonstrate that transcription of the gene encoding the coactivator PGC-1beta is C-MYC dependent and that loss of PGC-1beta expression is a major factor contributing to reduced respiration in VHL-deficient renal carcinoma cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Carrier Proteins / genetics
  • Cell Line, Tumor
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Mitochondria / metabolism*
  • Oxygen / metabolism
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myc / physiology
  • RNA, Messenger / genetics
  • RNA-Binding Proteins
  • Transcription, Genetic / physiology
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*


  • Carrier Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • PPARGC1B protein, human
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • RNA-Binding Proteins
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human
  • Oxygen