RRC ID 6832
著者 Liu X, Wang X, Zhang J, Lam EK, Shin VY, Cheng AS, Yu J, Chan FK, Sung JJ, Jin HC.
タイトル Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis.
ジャーナル Oncogene
Abstract 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.
巻・号 29(3)
ページ 442-50
公開日 2010-1-21
DOI 10.1038/onc.2009.332
PII onc2009332
PMID 19881551
MeSH 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
IF 7.971
引用数 124
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY GENETICS & HEREDITY ONCOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞 Kato III(RCB2088) MKN28(RCB1000) MKN45(RCB1001)