Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1

Mol Cell Biol. 2007 Nov;27(21):7381-93. doi: 10.1128/MCB.00440-07. Epub 2007 Sep 4.

Abstract

Hypoxia is a pervasive microenvironmental factor that affects normal development as well as tumor progression. In most normal cells, hypoxia stabilizes hypoxia-inducible transcription factors (HIFs), particularly HIF-1, which activates genes involved in anaerobic metabolism and angiogenesis. As hypoxia signals a cellular deprivation state, HIF-1 has also been reported to counter the activity of MYC, which encodes a transcription factor that drives cell growth and proliferation. Since many human cancers express dysregulated MYC, we sought to determine whether HIF-1 would in fact collaborate with dysregulated MYC rather countering its function. Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. We also found the collaborative induction of vascular endothelial growth factor (VEGF) by HIF-1 and dysregulated c-Myc. This study reports the previously unsuspected collaboration between HIF-1 and dysregulated MYC and thereby provides additional insights into the regulation of VEGF and the Warburg effect, which describes the propensity for cancer cells to convert glucose to lactate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromatin Immunoprecipitation
  • DNA / metabolism
  • Enzyme Induction
  • Glucose / metabolism
  • Glycolysis
  • Hexokinase / biosynthesis*
  • Hexokinase / genetics
  • Humans
  • Hypoxia-Inducible Factor 1 / metabolism*
  • Neoplasms / pathology
  • Protein Binding
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Regulatory Sequences, Nucleic Acid
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Hypoxia-Inducible Factor 1
  • Proto-Oncogene Proteins c-myc
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • DNA
  • Hexokinase
  • Protein-Serine-Threonine Kinases
  • Glucose