Carcinogenesis Advance Access published online on February 3, 2005
Carcinogenesis, doi:10.1093/carcin/bgi037
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
* To whom correspondence should be addressed. Folate is an essential co-factor in 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 mechanistically related to cancer development. Folate deficiency appears to increase the risk of several malignancies, and aberrant DNA methylation has been considered 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 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 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. Also, the effect of folate deficiency on DNA methylation appears to be mediated by both methionine cycle intermediate-dependent and independent pathways. 1 This project has been supported in part by a grant from the Canadian Institutes of Health Research (Grant # MOP-14126; to Y-I. K.) and a grant from the National Science Council of Taiwan (Grant #NSC 93-2320-B005-006; to E-P.C.). Young-In Kim is a recipient of a Scholarship from the Canadian Institutes of Health Research. Presented in part at the 2002 and 2003 American Association for Cancer Research Meeting, April 2002, San Francisco, CA and July 2003, Washington, DC, respectively, and published in abstract form in Proceedings of the American Association for Cancer Research 2002; 43: 521 (abst #2584) and 2003; 44: 890 (abst #3892).
Received October 29, 2004
Revised January 21, 2005
Accepted January 26, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model1
2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
3 Department of Food Science, National Chung Hsing University, Taichung, Taiwan; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720
4 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720
5 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 1A8; Department of Medicine, University of Toronto, Toronto, Ontario, Canada, M5S 1A8; Division of Gastroenterology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada, M5B 1W8
Young-In Kim, E-mail: youngin.kim{at}utoronto.ca
Abstract 
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]
|
|