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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
£169.00 per year
only £3.38 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aarenstrup L, Flindt EN, Otkjaer K, Kirkegaard M, Andersen JS, Kristiansen K . (2008). HDAC activity is required for p65/RelA-dependent repression of PPARdelta-mediated transactivation in human keratinocytes. J Invest Dermatol 128: 1095–1106.
Ashburner BP, Westerheide SD, Baldwin Jr AS . (2001). The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol 21: 7065–7077.
Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R et al. (2006). TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126: 107–120.
Bhat KP, Pelloski CE, Zhang Y, Kim SH, deLaCruz C, Rehli M et al. (2008). Selective repression of YKL-40 by NF-kappaB in glioma cell lines involves recruitment of histone deacetylase-1 and -2. FEBS Lett 582: 3193–3200.
Cheng YY, Jin H, Liu X, Siu JM, Wong YP, Ng EK et al. (2008). Fibulin 1 is downregulated through promoter hypermethylation in gastric cancer. Br J Cancer 99: 2083–2087.
Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R et al. (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452: 230–233.
Dang CV, Semenza GL . (1999). Oncogenic alterations of metabolism. Trends Biochem Sci 24: 68–72.
DeBerardinis RJ . (2008). Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genet Med 10: 767–777.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB . (2008a). The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11–20.
Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB . (2008b). Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 18: 54–61.
Eigenbrodt E, Reinacher M, Scheefers-Borchel U, Scheefers H, Friis R . (1992). Double role for pyruvate kinase type M2 in the expansion of phosphometabolite pools found in tumor cells. Crit Rev Oncog 3: 91–115.
Ferguson EC, Rathmell JC . (2008). New roles for pyruvate kinase M2: working out the Warburg effect. Trends Biochem Sci 33: 359–362.
Finco TS, Westwick JK, Norris JL, Beg AA, Der CJ, Baldwin Jr AS . (1997). Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J Biol Chem 272: 24113–24116.
Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T . (2000). DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24: 88–91.
Garber K . (2004). Energy boost: the Warburg effect returns in a new theory of cancer. J Natl Cancer Inst 96: 1805–1806.
Gatenby RA, Gillies RJ . (2004). Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891–899.
Green DR, Chipuk JE . (2006). p53 and metabolism: inside the TIGAR. Cell 126: 30–32.
Jin H, Sperka T, Herrlich P, Morrison H . (2006). Tumorigenic transformation by CPI-17 through inhibition of a merlin phosphatase. Nature 442: 576–579.
Jurica MS, Mesecar A, Heath PJ, Shi W, Nowak T, Stoddard BL . (1998). The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure 6: 195–210.
Karnoub AE, Weinberg RA . (2008). Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9: 517–531.
Kawauchi K, Araki K, Tobiume K, Tanaka N . (2008). p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 10: 611–618.
Kondoh H, Lleonart ME, Gil J, Wang J, Degan P, Peters G et al. (2005). Glycolytic enzymes can modulate cellular life span. Cancer Res 65: 177–185.
Koshiba M, Ogawa O, Habuchi T, Hamazaki S, Shimada T, Takahashi R et al. (1993). Infrequent ras mutation in human stomach cancers. Jpn J Cancer Res 84: 163–167.
Lee MG, Pedersen PL . (2003). Glucose metabolism in cancer: importance of transcription factor-DNA interactions within a short segment of the proximal region og the type II hexokinase promoter. J Biol Chem 278: 41047–41058.
Marin-Hernandez A, Rodriguez-Enriquez S, Vital-Gonzalez PA, Flores-Rodriguez FL, Macias-Silva M, Sosa-Garrocho M et al. (2006). Determining and understanding the control of glycolysis in fast-growth tumor cells. Flux control by an over-expressed but strongly product-inhibited hexokinase. FEBS J 273: 1975–1988.
Mathupala SP, Ko YH, Pedersen PL . (2008). Hexokinase-2 bound to mitochondria: cancer's stygian link to the ‘Warburg Effect’ and a pivotal target for effective therapy. Semin Cancer Biol 19: 17–24.
Mazurek S, Zwerschke W, Jansen-Durr P, Eigenbrodt E . (2001). Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and HPV-16 E7. Oncogene 20: 6891–6898.
Peng SY, Lai PL, Pan HW, Hsiao LP, Hsu HC . (2008). Aberrant expression of the glycolytic enzymes aldolase B and type II hexokinase in hepatocellular carcinoma are predictive markers for advanced stage, early recurrence and poor prognosis. Oncol Rep 19: 1045–1053.
Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP . (2000). DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25: 338–342.
Rountree MR, Bachman KE, Baylin SB . (2000). DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25: 269–277.
Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E . (2004). The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res 64: 2627–2633.
Tannock IF . (1968). The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 22: 258–273.
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM . (1996). Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274: 787–789.
Vaupel P, Kallinowski F, Okunieff P . (1989). Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449–6465.
Wang LJ, Jin HC, Wang X, Lam EK, Zhang JB, Liu X et al. (2009). ZIC1 is downregulated through promoter hypermethylation in gastric cancer. Biochem Biophys Res Commun 379: 959–963.
Warburg O . (1956). On the origin of cancer cells. Science 123: 309–314.
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2009.332