Article: Warburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis
| Title | Warburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Liu, X3 Wang, X1 Zhang, J3 Lam, EKY3 Shin, VY3 Cheng, ASL3 Yu, J2 Chan, FKL2 Sung, JJY2 Jin, HC1 3 | ||||||
| Issue Date | 2010 | ||||||
| Publisher | Nature 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?] DOI: http://dx.doi.org/10.1038/onc.2009.332 | ||||||
| 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. © 2010 Macmillan Publishers Limited All rights reserved. | ||||||
| ISSN | 0950-9232 2011 Impact Factor: 6.373 2011 SCImago Journal Rankings: 1.216 | ||||||
| DOI | http://dx.doi.org/10.1038/onc.2009.332 | ||||||
| ISI Accession Number ID | WOS:000273793200013
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.contributor.author | Liu, X | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Wang, X | ||||||
| dc.contributor.author | Zhang, J | ||||||
| dc.contributor.author | Lam, EKY | ||||||
| dc.contributor.author | Shin, VY | ||||||
| dc.contributor.author | Cheng, ASL | ||||||
| dc.contributor.author | Yu, J | ||||||
| dc.contributor.author | Chan, FKL | ||||||
| dc.contributor.author | Sung, JJY | ||||||
| dc.contributor.author | Jin, HC | ||||||
| dc.date.accessioned | 2011-10-28T02:50:46Z | ||||||
| dc.date.available | 2011-10-28T02:50:46Z | ||||||
| dc.date.issued | 2010 | ||||||
| dc.description.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. © 2010 Macmillan Publishers Limited All rights reserved. | ||||||
| dc.description.nature | Link_to_subscribed_fulltext | ||||||
| dc.identifier.citation | Oncogene, 2010, v. 29 n. 3, p. 442-450 [How to Cite?] DOI: http://dx.doi.org/10.1038/onc.2009.332 | ||||||
| dc.identifier.citeulike | 6065960 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1038/onc.2009.332 | ||||||
| dc.identifier.epage | 450 | ||||||
| dc.identifier.hkuros | 184628 | ||||||
| dc.identifier.isi | WOS:000273793200013
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.issn | 0950-9232 2011 Impact Factor: 6.373 2011 SCImago Journal Rankings: 1.216 | ||||||
| dc.identifier.issue | 3 | ||||||
| dc.identifier.pmid | 19881551 | ||||||
| dc.identifier.scopus | eid_2-s2.0-75149159101 | ||||||
| dc.identifier.spage | 442 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/142538 | ||||||
| dc.identifier.volume | 29 | ||||||
| dc.language | eng | ||||||
| dc.publisher | Nature Publishing Group. The Journal's web site is located at http://www.nature.com/onc | ||||||
| dc.relation.ispartof | Oncogene | ||||||
| dc.subject.mesh | Cell Transformation, Neoplastic - genetics - metabolism | ||||||
| dc.subject.mesh | Epigenesis, Genetic | ||||||
| dc.subject.mesh | Fructose-Bisphosphatase - genetics - metabolism | ||||||
| dc.subject.mesh | Glycolysis | ||||||
| dc.subject.mesh | Stomach Neoplasms - genetics - metabolism - pathology | ||||||
| dc.title | Warburg effect revisited: An epigenetic link between glycolysis and gastric carcinogenesis | ||||||
| dc.type | Article |
Author Affiliations
- Zhejiang University School of Medicine
- Prince of Wales Hospital Hong Kong
- Chinese University of Hong Kong