Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis.
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.
Liu
X
X
Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
Wang
X
X
Zhang
J
J
Lam
E K Y
EK
Shin
V Y
VY
Cheng
A S L
AS
Yu
J
J
Chan
F K L
FK
Sung
J J Y
JJ
Jin
H C
HC
D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D006597:Fructose-Bisphosphatase / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D053208:Kaplan-Meier Estimate; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D019344:Lactic Acid; D006597:Fructose-Bisphosphatase; D018631:ras Proteins; D005947:Glucose