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Article: Warburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis
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TitleWarburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis
 
AuthorsLiu, X3
Wang, X1
Zhang, J3
Lam, EKY3
Shin, VY3
Cheng, ASL3
Yu, J2
Chan, FKL2
Sung, JJY2
Jin, HC1 3
 
Issue Date2010
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
CitationOncogene, 2010, v. 29 n. 3, p. 442-450 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2009.332
 
AbstractIn 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. © 2010 Macmillan Publishers Limited All rights reserved.
 
ISSN0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
DOIhttp://dx.doi.org/10.1038/onc.2009.332
 
ISI Accession Number IDWOS:000273793200013
Funding AgencyGrant Number
RGC-GRF465808
Institute of Digestive Disease, the Chinese University of Hong Kong
Funding Information:

The project was supported by RGC-GRF ( Project No. 465808) granted to HJ, and Research Funding from the Institute of Digestive Disease, the Chinese University of Hong Kong.

 
DC FieldValue
dc.contributor.authorLiu, X
 
dc.contributor.authorWang, X
 
dc.contributor.authorZhang, J
 
dc.contributor.authorLam, EKY
 
dc.contributor.authorShin, VY
 
dc.contributor.authorCheng, ASL
 
dc.contributor.authorYu, J
 
dc.contributor.authorChan, FKL
 
dc.contributor.authorSung, JJY
 
dc.contributor.authorJin, HC
 
dc.date.accessioned2011-10-28T02:50:46Z
 
dc.date.available2011-10-28T02:50:46Z
 
dc.date.issued2010
 
dc.description.abstractIn 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. © 2010 Macmillan Publishers Limited All rights reserved.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationOncogene, 2010, v. 29 n. 3, p. 442-450 [How to Cite?]
DOI: http://dx.doi.org/10.1038/onc.2009.332
 
dc.identifier.citeulike6065960
 
dc.identifier.doihttp://dx.doi.org/10.1038/onc.2009.332
 
dc.identifier.epage450
 
dc.identifier.hkuros184628
 
dc.identifier.isiWOS:000273793200013
Funding AgencyGrant Number
RGC-GRF465808
Institute of Digestive Disease, the Chinese University of Hong Kong
Funding Information:

The project was supported by RGC-GRF ( Project No. 465808) granted to HJ, and Research Funding from the Institute of Digestive Disease, the Chinese University of Hong Kong.

 
dc.identifier.issn0950-9232
2013 Impact Factor: 8.559
2013 SCImago Journal Rankings: 4.764
 
dc.identifier.issue3
 
dc.identifier.pmid19881551
 
dc.identifier.scopuseid_2-s2.0-75149159101
 
dc.identifier.spage442
 
dc.identifier.urihttp://hdl.handle.net/10722/142538
 
dc.identifier.volume29
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
 
dc.relation.ispartofOncogene
 
dc.subject.meshCell Transformation, Neoplastic - genetics - metabolism
 
dc.subject.meshEpigenesis, Genetic
 
dc.subject.meshFructose-Bisphosphatase - genetics - metabolism
 
dc.subject.meshGlycolysis
 
dc.subject.meshStomach Neoplasms - genetics - metabolism - pathology
 
dc.titleWarburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis
 
dc.typeArticle
 
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<contributor.author>Wang, X</contributor.author>
<contributor.author>Zhang, J</contributor.author>
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<contributor.author>Shin, VY</contributor.author>
<contributor.author>Cheng, ASL</contributor.author>
<contributor.author>Yu, J</contributor.author>
<contributor.author>Chan, FKL</contributor.author>
<contributor.author>Sung, JJY</contributor.author>
<contributor.author>Jin, HC</contributor.author>
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Author Affiliations
  1. Zhejiang University School of Medicine
  2. Prince of Wales Hospital Hong Kong
  3. Chinese University of Hong Kong