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Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis

Oncogene volume 29, pages 442–450 (2010)Cite this article

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.

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Acknowledgements

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.

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  1. X Liu and X Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China

    X Liu, J Zhang, E K Y Lam, V Y Shin, A S L Cheng & H C Jin

  2. Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China

    X Wang

  3. Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China

    J Yu, F K L Chan & J J Y Sung

  4. Biomedical Research Center, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China

    H C Jin

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Correspondence to H C Jin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Liu, X., Wang, X., Zhang, J. et al. Warburg effect revisited: an epigenetic link between glycolysis and gastric carcinogenesis. Oncogene 29, 442–450 (2010). https://doi.org/10.1038/onc.2009.332

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