Carcinogenesis Advance Access originally published online on February 3, 2005
Carcinogenesis 2005 26(5):981-990; doi:10.1093/carcin/bgi037
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis vol.26 no.5 © Oxford University Press 2005; all rights reserved.
Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model
1 Departments of Nutritional Sciences and 2 Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8, 3 Division of Gastroenterology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada, M5B 1W8, 4 Department of Food Science, National Chung Hsing University, Taichung, Taiwan and 5 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA
* To whom requests for reprints should be addressed at: Room 7258, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8, Tel: +1 416 978 1183; Fax: +1 416 978 8765; Email: youngin.kim{at}utoronto.ca
Folate is an essential co-factor in the remethylation of homocysteine to methionine, thereby ensuring the supply of S-adenosylmethionine, the methyl group donor for most biological methylations, including that of DNA. Aberrant patterns and dysregulation of DNA methylation are consistent events in carcinogenesis and hence, DNA methylation is considered to be mechanistically related to the development of cancer. Folate deficiency appears to increase the risk of several malignancies, and aberrant DNA methylation has been considered to be a leading mechanism by which folate deficiency enhances carcinogenesis. Although diets deficient in methyl group donors (choline, folate, methionine and vitamin B12) have been consistently observed to induce DNA hypomethylation, the effect of an isolated folate deficiency on DNA methylation remains highly controversial and unresolved. Whether or not isolated folate deficiency can modulate DNA methylation is an important issue because it would establish a mechanistic link between folate deficiency and cancer. We examined the effects of isolated folate deficiency on methionine cycle intermediates, genomic and site-specific DNA methylation and DNA methyltransferase in an in vitro model of folate deficiency, using untransformed NIH/3T3 and CHO-K1 cells, and human HCT116 and Caco-2 colon cancer cells. Our data demonstrate that the effect of folate deficiency on the methionine cycle pathway and DNA methylation in these cells is highly complex and appears to depend on the cell type and stage of transformation, and may be gene and site-specific. The direction of changes of methionine cycle intermediates in response to folate deficiency is not uniformly consistent with the known biochemical effect of folate on the methionine cycle pathway. Moreover, the effect of folate deficiency on DNA methylation appears to be mediated by both methionine cycle intermediate-dependent and independent pathways.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Kotsopoulos, K.-J. Sohn, and Y.-I. Kim Postweaning Dietary Folate Deficiency Provided through Childhood to Puberty Permanently Increases Genomic DNA Methylation in Adult Rat Liver J. Nutr., April 1, 2008; 138(4): 703 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Curtin, M. L. Slattery, C. M. Ulrich, J. Bigler, T. R. Levin, R. K. Wolff, H. Albertsen, J. D. Potter, and W. S. Samowitz Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet Carcinogenesis, August 1, 2007; 28(8): 1672 - 1679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. F. Woeller, D. D. Anderson, D. M. E. Szebenyi, and P. J. Stover Evidence for Small Ubiquitin-like Modifier-dependent Nuclear Import of the Thymidylate Biosynthesis Pathway J. Biol. Chem., June 15, 2007; 282(24): 17623 - 17631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Hayashi, K.-J. Sohn, J. M. Stempak, R. Croxford, and Y.-I. Kim Folate Deficiency Induces Cell-Specific Changes in the Steady-State Transcript Levels of Genes Involved in Folate Metabolism and 1-Carbon Transfer Reactions in Human Colonic Epithelial Cells J. Nutr., March 1, 2007; 137(3): 607 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Marsit, K. Eddy, and K. T. Kelsey MicroRNA Responses to Cellular Stress. Cancer Res., November 15, 2006; 66(22): 10843 - 10848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Wasson, A. P. McGlynn, H. McNulty, S. L. O'Reilly, V. J. McKelvey-Martin, G. McKerr, J. J. Strain, J. Scott, and C. S. Downes Global DNA and p53 Region-Specific Hypomethylation in Human Colonic Cells Is Induced by Folate Depletion and Reversed by Folate Supplementation J. Nutr., November 1, 2006; 136(11): 2748 - 2753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Leopardi, F. Marcon, S. Caiola, A. Cafolla, E. Siniscalchi, A. Zijno, and R. Crebelli Effects of folic acid deficiency and MTHFR C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes Mutagenesis, September 1, 2006; 21(5): 327 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Novakovic, J. M. Stempak, K.-J. Sohn, and Y.-I. Kim Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells Carcinogenesis, May 1, 2006; 27(5): 916 - 924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-I. Kim Nutritional Epigenetics: Impact of Folate Deficiency on DNA Methylation and Colon Cancer Susceptibility J. Nutr., November 1, 2005; 135(11): 2703 - 2709. [Abstract] [Full Text] [PDF]
|
|