Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis

Oncogene. 2010 Jan 21;29(3):442-50. doi: 10.1038/onc.2009.332. Epub 2009 Nov 2.


In cancer cells, glucose is often converted into lactic acid, which is known as the 'Warburg effect'. The reason that cancer cells have a higher rate of aerobic glycolysis, but not oxidative phosphorylation, remains largely unclear. Herein, we proposed an epigenetic mechanism of the Warburg effect. Fructose-1,6-bisphosphatase-1 (FBP1), which functions to antagonize glycolysis was downregulated through NF-kappaB pathway in Ras-transformed NIH3T3 cells. Restoration of FBP1 expression suppressed anchorage-independent growth, indicating the relevance of FBP1 downregulation in carcinogenesis. Indeed, FBP1 was downregulated in gastric carcinomas (P<0.01, n=22) and gastric cancer cell lines (57%, 4/7). Restoration of FBP1 expression reduced growth and glycolysis in gastric cancer cells. Moreover, FBP1 downregulation was reversed by pharmacological demethylation. Its promoter was hypermethylated in gastric cancer cell lines (57%, 4/7) and gastric carcinomas (33%, 33/101). Inhibition of NF-kappaB restored FBP1 expression, partially through demethylation of FBP1 promoter. Notably, Cox regression analysis revealed FBP1 promoter methylation as an independent prognosis predicator for gastric cancer (hazard ratio: 3.60, P=0.010). In summary, we found that NF-kappaB functions downstream of Ras to promote epigenetic downregulation of FBP1. Promoter methylation of FBP1 can be used as a new biomarker for prognosis prediction of gastric cancer. Such an important epigenetic link between glycolysis and carcinogenesis partly explains the Warburg effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • DNA Methylation
  • Down-Regulation
  • Epigenesis, Genetic*
  • Female
  • Fructose-Bisphosphatase / genetics*
  • Fructose-Bisphosphatase / metabolism
  • Glucose / metabolism
  • Glycolysis*
  • Humans
  • Kaplan-Meier Estimate
  • Lactic Acid / metabolism
  • Male
  • Mice
  • Middle Aged
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • NIH 3T3 Cells
  • Prognosis
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • NF-kappa B
  • Lactic Acid
  • Fructose-Bisphosphatase
  • ras Proteins
  • Glucose