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Article: Warburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis

TitleWarburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis
Authors
Issue Date2010
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc
Citation
Oncogene, 2010, v. 29 n. 3, p. 442-450 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/142538
ISSN
2014 Impact Factor: 8.459
2014 SCImago Journal Rankings: 3.643
ISI Accession Number ID
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 FieldValueLanguage
dc.contributor.authorLiu, Xen_US
dc.contributor.authorWang, Xen_US
dc.contributor.authorZhang, Jen_US
dc.contributor.authorLam, EKYen_US
dc.contributor.authorShin, VYen_US
dc.contributor.authorCheng, ASLen_US
dc.contributor.authorYu, Jen_US
dc.contributor.authorChan, FKLen_US
dc.contributor.authorSung, JJYen_US
dc.contributor.authorJin, HCen_US
dc.date.accessioned2011-10-28T02:50:46Z-
dc.date.available2011-10-28T02:50:46Z-
dc.date.issued2010en_US
dc.identifier.citationOncogene, 2010, v. 29 n. 3, p. 442-450en_US
dc.identifier.issn0950-9232-
dc.identifier.urihttp://hdl.handle.net/10722/142538-
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.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/onc-
dc.relation.ispartofOncogeneen_US
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 carcinogenesisen_US
dc.typeArticleen_US
dc.identifier.emailShin, VY: vyshin@hku.hken_US
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/onc.2009.332-
dc.identifier.pmid19881551-
dc.identifier.scopuseid_2-s2.0-75149159101-
dc.identifier.hkuros184628en_US
dc.identifier.volume29en_US
dc.identifier.issue3en_US
dc.identifier.spage442en_US
dc.identifier.epage450en_US
dc.identifier.isiWOS:000273793200013-
dc.identifier.citeulike6065960-

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