![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
3
*
Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University and
Divisions of Clinical Nutrition and Gastroenterology, Tufts University School of Medicine, Boston, MA 02111
3To whom correspondence should be addressed. E-mail: jmason{at}hnrc.tufts.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONDISCUSSIONLITERATURE CITED |
|---|
KEY WORDS: • folate • colon carcinogenesis • methylenetetrahydrofolate reductase • DNA methylation
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONDISCUSSIONLITERATURE CITED |
|---|
). Folate deficiency also has been considered an important factor in alcohol-related carcinogenesis, because alcohol alters normal folate metabolism in a number of ways (2
).
Folate has a central role in one-carbon metabolism. As such, it is a critical coenzyme for both biological methylation and nucleotide synthesis (Fig. 1
). These are important functions, because aberrations in the methylation of macromolecules, particularly DNA, as well as disruption in DNA synthesis and repair, are thought to play major roles in carcinogenesis (reviewed in reference 3
). Methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20),4
a key enzyme in one-carbon metabolism (Fig. 1)
, catalyzes a unidirectional reaction that determines the balance between cellular availability of 5,10-methylenetetrahydrofolate (5,10-methylene THF), which is used for thymidylate and purine synthesis, and methyl-THF, which is used for biological methylation. Recently, a highly prevalent polymorphism of the MTHFR gene has been described and reported to have a strong relationship with cancer risk. Not surprisingly, the relationship with cancer risk is modified by folate status (4
).
|
). The evolving hypothesis, supported by observations from many laboratories, is that folate depletion enhances carcinogenesis by impairing normal methylation and nucleotide synthesis by creating an imbalance between the partitioning of cellular folates down these two pathways. |
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONDISCUSSIONLITERATURE CITED |
|---|
One-carbon metabolism is a network of interrelated biochemical reactions in which a one-carbon unit from a donor compound is transferred to tetrahydrofolate (THF) for subsequent reduction or oxidation and/or transfer to other compounds (Fig. 1)
. Folate coenzymes in mammalian tissues thereby act as acceptors or donors of one-carbon units in a variety of reactions involved in amino acid and nucleotide metabolism (5
). Three of the one-carbon substituted derivatives of THF are each associated with metabolic pathways that are particularly important to that particular form of the vitamin: methyl-THF is needed for methionine synthesis (which is necessary for DNA methylation), 5,10-methyleneTHF for thymidylate synthesis, and 10-formyltetrahydrofolate for purine synthesis (6
).
Methionine synthesis plays a major role in one-carbon metabolism (Fig. 1)
. Methionine is regenerated from homocysteine in a reaction catalyzed by methionine synthase (5-methyltetrahydrofolate—homocysteine S-methyltransferase; EC 2.1.1.13): this is the only known reaction in which the methyl group of methyl-THF is used in mammalian tissues. The enzyme contains a cobalamin (B-12) cofactor, and the reaction proceeds via a methylcobalamin intermediate (7
). Regenerated methionine is then adenylated to form S-adenosylmethionine (SAM). SAM then donates its labile methyl group to more than 80 biological methylation reactions, including the methylation of DNA, RNA and protein. Although the alternative betaine pathway for methionine synthesis may partially compensate, it is nevertheless well known that dietary folate depletion alone is a sufficient perturbing force to diminish SAM pools (8
). As described in the next section, experimental folate depletion in both animals and humans produces demonstrable impairments in biological methylation (9
,10
).
Folate-derived one-carbon metabolism also is essential for the synthesis of nucleotides. Thymidylate synthase catalyzes the transfer of formaldehyde from folate to the 5-position of deoxyuridylate, producing deoxythymidylate. In addition, one-carbon moieties at the oxidation level of formate are used in de novo purine biosynthesis. Because deoxynucleotides are the immediate substrates for the polymerases involved in DNA replication and repair, the fidelity of DNA synthesis is critically dependent on the correct balance and availability of deoxynucleotides (3
). In mammalian cells, the de novo synthesis of deoxythymidylate from deoxyuridylate is a rate-limiting step for DNA synthesis. In cells, inhibition of folate metabolism results in uracil misincorporation in DNA (11
). Recently, it has been shown that folate deficiency in the human results in excess uracil incorporation into DNA (12
).
Folate and DNA methylation.
Approximately 4% of all cytosines in mammalian DNA are methylated. Most of these 5-methyldeoxycytidine (5-MC) residues are found in the palindromic sequence, cytosine guanine dinucleotide (CpG) (13
). Maintenance of normal patterns of DNA methylation is important for cellular homeostasis because DNA methylation is thought to play critical roles in the regulation of gene expression and gene integrity (14
).
Accumulating evidence implicates aberrations in DNA methylation as a cause of carcinogenesis rather than as just an epiphenomenon. A decreased level of genomic methylation is a nearly universal finding in tumorigenesis: this has been observed in cancers of the colon, stomach, uterine cervix, prostate, thyroid and breast (reviewed in reference 1
). This decrease in genomic methylation appears early in carcinogenesis and, at least in the case of colorectal cancer, seems to precede the better described mutation and deletion events that occur later in the evolution of cancer (15
). However, DNA methylation does not seem to be confined solely to the neoplasm. It has been observed to be present in normal-appearing rectosigmoid mucosa of patients harboring adenomas or carcinomas and therefore seems to be a characteristic of colonic mucosa that is predisposed to undergo neoplastic transformation. Whether it is responsible for that predisposition remains a matter of speculation. Genomic hypomethylation of DNA also has been observed in the colonic mucosa of animals genetically engineered to develop intestinal neoplasms (16
), as well as in rats exposed to the colonic carcinogen dimethylhydrazine (17
).
In 1993 Balaghi and Wagner demonstrated that hepatic DNA from folate deficient rats was hypomethylated on a genomic level compared with DNA from pair-fed control animals (9
). When this phenomenon has been reexamined in the liver (18
) or in other tissues such as the colon (19
), the effect has not always been reproduced; therefore, it may be dependent on the severity or duration of the deficiency and/or it may be a tissue-specific effect.
In human studies using lymphocytic DNA, a consistent relationship between folate status and genomic DNA methylation has been observed. Jacob and colleagues reported that marginal folate depletion in volunteers housed in a metabolic unit diminished genomic DNA methylation; repletion of folate status then reversed the hypomethylation (10
). Rampersaud and colleagues reported a similar effect in their metabolic unit study where a less restrictive diet (120 µg folate/d) was used (20
). The induction of genomic hypomethylation under these circumstances probably is due primarily to the associated rise in homocysteine, which in turn increases tissue concentrations of S-adenosylhomocysteine (SAH), an inhibitor of methylation reactions (21
). It is for this reason that plasma SAH and not SAM concentrations have been found to be most predictive of DNA methylation (22
).
From the perspective of carcinogenesis, hypomethylation at critical loci is probably a more important factor than genomic hypomethylation. Observations in folate-deficient rats have confirmed that dietary deprivation of folate is a sufficient force to produce hypomethylation within the "hypermutable region" of the p53 gene (18
). Subsequent studies have demonstrated that this depletion also decreases steady-state concentrations of p53 mRNA (23
). Consistent with the concept that these changes are involved in carcinogenesis are observations which indicate that hypomethylation within exon 8 of the colonic p53 gene is also observed in an animal model of chemical carcinogenesis. Most recently, Jhaveri and colleagues reported that folate depletion produces gene-specific, rather than genomic, DNA hypomethylation in human nasopharyngeal carcinoma KB cells (24
). Cell culture studies indicate that these foci of aberrant methylation within the coding region may serve as initiators of mutation (25
) and may induce susceptibility to breakage of the DNA backbone at the site of hypomethylation (26
) by increased uracil insertion and strand breaks (12
). Hypomethylation of the coding regions of critical genes, which have been observed experimentally in models of folate depletion (18
), can lead to instability of the region either because it becomes more susceptible to endogenous nucleases (27
) or because the site of hypomethylation is more likely to undergo deamination to uracil (11
,12
). The latter situation is particularly prone to occur under conditions in which intracellular SAM concentrations are low, such as in folate depletion (28
).
Alterations in methylation status within promoter regions is a very important epigenetic mechanism in gene control (29
). Because methylation of the promoter generally suppresses transcription, promoter hypomethylation can activate protooncogenes, and promoter hypermethylation can inactivate tumor suppressor genes. In a rat model of hepatocellular carcinoma, a choline-deficient diet induced hypomethylation of 5' upstream CpG sites of the c-myc gene as well as over expression of this gene (30
). Interestingly, experimental deficiency of one-carbon nutrients in animals may instead cause a paradoxical (and presumably compensatory) hypermethylation of certain loci (31
), which is of interest because the promoter regions of several tumor suppressor genes, such as p16, p53, and APC, are frequently found to be hypermethylated in cancers (32
–34
). Jhaveri and colleagues also reported that the H-cadherin gene, which showed hypermethylation of 5' sequences in response to folate depletion, was down-regulated in human nasopharyngeal carcinoma KB cells. This hypermethylation suppresses expression of the gene (35
) and is therefore hypothesized to contribute to the evolution of the cancer.
The importance of promoter methylation of tumor suppressor genes in cancer is underscored (36
) by the following observations: 1) gene silencing associated with promoter hypermethylation is a fully heritable event for individual alleles of a given gene. For examples, in cell culture, a mutated copy of the p16 gene allele that has an unmethylated promoter is expressed, whereas the wild-type allele is hypermethylated and silenced (37
); 2) hypermethylation of promoters nearly always occurs only in those tumors that lack coding-region mutations in the involved gene (38
); and 3) the selective survival advantage for a clone of cells that has undergone a loss of function associated with altered methylation seems to be identical to the loss of function arising from a coding-region mutation (38
).
Folate and DNA synthesis/repair.
It has been known for some decades that folate deficiency induces breaks in chromosomes and that such breaks are associated with an increased risk of cancer in humans. DNA strand breaks, whereby breaks occur in the phosphodiesterase backbone of DNA, seem to be the molecular basis for this disruption in chromosomal integrity. Folate-deficient conditions in both cell culture (39
) and animal experiments (26
) have been shown to create an excess of strand breaks in DNA (39
). In a study of rats, a folate-deficient diet increased gene-specific DNA strand breaks in the hypermutable region of p53 in the rat colon (18
) and decreased steady-state p53 gene expression in that organ (23
). Preliminary data from a human study also indicate that genome-wide DNA strand breaks are related to folate status (40
).
Two likely mechanisms by which folate deficiency may create such breaks are uracil misincorporation (41
) and impaired DNA repair (42
). Folate deficiency reduces deoxythymidylate synthesis from deoxyuridylate, and the ensuing nucleotide imbalance increases the incorporation of uracil bases into DNA. Uracil in DNA is excised by a repair glycosylase and, in the process, a transient single-strand break develops in the DNA (12
). Simultaneous removal and repair of two adjacent uracil residues on opposite strands can result in a double-strand DNA break, which is difficult to repair and further exacerbates genetic instability. Unrepaired double-strand DNA breaks enhance cellular transformation in culture and increase cancer risk. Similarly, an in vitro study using immortalized human colon epithelial cells demonstrated that folate deficiency induces uracil misincorporation and increases DNA strand breaks (41
). Excessive DNA uracil content, as well as increased numbers of chromosomal breaks, are observed in folate deficient humans, and both defects are reversed by folate administration (12
). Increased DNA strand breaks induced by folate depletion also seem to arise as a result of impaired DNA repair. In a folate-deficient rat model, DNA excision repair was impaired in deficient colonic mucosal cells compared with normal mucosal cells (42
). Fenech and colleagues (43
) also found that folate supplementation above the recommended dietary allowance lessened chromosome breakage below concentrations observed in healthy, folate-replete persons. They suggest that this is an indication that basal requirements of folate are higher than formerly thought.
Folate and cell proliferation.
Folate status also affects cell proliferation. Abnormal cell proliferation has essential roles in carcinogenesis, including the processes of initiation and promotion, although its precise role is still not clarified (44
). A net increase in cell division is undesirable because it is generally agreed that it leads to hyperplastic and/or neoplastic growth. During clonal expansion, proliferating cells divide by a process defined by the cell cycle, which is strictly controlled at several check points by numerous oncoproteins, tumor suppressor gene proteins, and cyclins.
Folate status, in many settings, modifies proliferation rates. James and colleagues reported increased excess proliferation in the livers of folate/methyl-deficient rats (45
). Conversely, folate supplementation has been observed to decrease colorectal mucosal proliferation in both animal and human studies. Nensey and colleagues reported that in an animal model, folate supplementation reduces carcinogen-induced ornithine decarboxylase and tyrosine kinase activity, both of which are indices of cellular proliferation (46
). Biasco and colleagues also reported that folate supplementation significantly reduces rectal mucosal proliferation in patients with long-standing ulcerative colitis, a condition that carries an increased risk of colorectal cancer, a predisposition to which is thought to be due in part to reduced availability of folate (47
). Most recently, Akoglu and colleagues reported a human colon cancer cell line in which dihydrofolate and methyl-THF served as growth-inhibitory factors (48
).
Cell proliferation is affected by DNA methylation. Fournel and colleagues reported that specific reduction of cellular DNA methyltransferase in human cancer cells inhibits cell proliferation (49
). DNA hypomethylation at critical loci might enhance expression of proto-oncogenes, such as ras and c-myc, or other genes related to carcinogenesis, resulting in excess cell proliferation (50
,51
).
Aberrations in folate form distribution: the MTHFR polymorphism.
Qualitative changes in folate metabolism may be as important as quantitative changes in regard to carcinogenesis. For example, MTHFR catalyzes the irreversible conversion of 5,10-methylene THF to methyl-THF. A common polymorphism of this gene (cytosine-to-thymine transition at position 677 or C677T) causes reduced activity of MTHFR (52
). In 1997 Ma and colleagues (4
) reported that folate-replete men who are homozygous for the mutation (TT) have half the risk of colorectal cancer compared with the wild-type and heterozygous genotypes. However, protection associated with the mutation was absent in men with low systemic folate status. Subsequent confirmations of this observation suggest that the homozygote may be at even greater risk of cancer than the wild-type subject when folate status is low (53
). Several epidemiologic studies indicate that the relationship between this polymorphism and cancer may also exist for other tissues, such as esophagus, lung, bone marrow, breast and ovary (54
–56
).
It has been suggested that the cancer-protective effect of the MTHFR mutation in folate-replete conditions is related to the increased availability of 5,10-methylene THF and, therefore, increased ease of nucleotide synthesis. On the other hand, the increased risk of colorectal cancer apparent in TT subjects with low folate status may be because of the fact that, below a certain threshold, availability of methyl-THF for biological methylation becomes compromised severely enough to become the critical determinant of whether the cell is pushed down the pathway toward neoplasia (3
). Bagley and colleagues reported that persons homozygous for the polymorphism have lower proportions of methylated folates in their red cells (57
). This qualitative change, even in the absence of any quantitative differences in cellular folate carcinogenesis, is associated with reductions in genomic DNA methylation, as previously shown in a small population (58
) and now confirmed in a large cohort (59
).
Thus, the modulation of cancer risk associated with the polymorphism may be conveyed by a shift in proportions of the different coenzymatic forms of folate contained within the cell, thereby changing the balance of biological methylation and DNA synthesis/repair. Qualitative alterations in cellular folate pools related to genotype also may explain how the protective effect associated with the mutant genotype is operable even in the face of plentiful quantities of cellular folate in folate-replete subjects. Therefore, under certain conditions, alterations in folate form distribution (i.e., a qualitative change in folate metabolism) might be more important than total folate concentrations (i.e., a quantitative change) in determining the risk of carcinogenesis (60
).
Folate, homocysteine and carcinogenesis.
Hyperhomocysteinemia, which is indicative of an impairment of one-carbon metabolism, has been regarded as an important risk factor for cardiovascular disease but as not significant in cancer. However, Kato and colleagues reported in a nested case-control study that the risk of colorectal cancer was significantly elevated among those with a higher total plasma homocysteine concentration. With multivariate analysis, there was a strong trend toward an effect of total plasma homocysteine that was independent of folate concentrations (61
). Weinstein and colleagues also reported in a large case-control study that invasive cervical cancer risk is significantly increased for women with high homocysteine concentrations (62
). Consistent with earlier studies, Yi and colleagues demonstrated that chronic elevations in plasma homocysteine concentrations, such as those associated with nutritional deficiencies or genetic polymorphisms in the folate pathway, may have an indirect and negative effect on cellular methylation reactions through a concomitant increase in intracellular SAH concentrations (22
). Because SAH inhibits biological methylation reactions, increased homocysteine concentrations may directly affect carcinogenesis by diminishing DNA methylation in critical tissues.
In conclusion, compelling evidence indicates that folate status modulates the risk of developing colorectal cancer: folate depletion seems to enhance carcinogenesis, and folate supplementation conveys a protective effect. However, two decades of studies have not yet defined the mechanism(s) responsible for mediating this effect. Nevertheless, such an understanding is being approached.
Because folate has a critical role in both DNA methylation and DNA synthesis, most studies have focused on these effects. Interestingly, alterations in DNA methylation, an epigenetic phenomenon that can affect gene expression and integrity, have been found in folate-depletion studies in both humans and animals. Increased uracil incorporation into DNA, which reflects an imbalance of nucleotide synthesis and can induce DNA strand breaks, also has been observed in human studies that have examined folate-deplete subjects. Both phenomena can be reversed by folate supplementation.
These two mechanisms are highlighted by the common polymorphism of the MTHFR gene and the remarkable decrease in the incidence of colorectal cancer associated with it. This is presumably because the MTHFR reaction sits as a fulcrum between DNA methylation and DNA synthesis, balancing the two pathways to maintain normal homeostasis.
|
FOOTNOTES |
|---|
2 This material is based upon work supported by the U. S. Department of Agriculture, under agreement No. 581950-9-001. Any opinions, findings, conclusions or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the U. S. Department of Agriculture.
4 Abbreviations used: 5-MC, 5-methyldeoxycytidine; CpG, cytosine guanine dinucleotide; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; THF, tetrahydrofolate; TT, thymine/thymine.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTINTRODUCTIONDISCUSSIONLITERATURE CITED |
|---|
1. Kim, Y. I. (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J. Nutr. Biochem 10:66-88.[Medline]
2. Halsted, C. H. (1995) Alcohol and folate interactions: clinical implications. Bailey, L. B. eds. Folate in Health and Disease 1995:313-327 Marcel Dekker New York, NY. .
3. Choi, S. W. & Mason, J. B. (2000) Folate and carcinogenesis: an integrated scheme. J. Nutr. 130:129-132.
4. Ma, J., Stampfer, M. J., Giovannucci, E., Artigas, C., Hunter, D. J., Fuchs, C., Willett, W. C., Selhub, J., Hennekens, C. H. & Rozen, R. (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res 57:1098-1102.
5. MacKenzie, R. E. (1984) Biogenesis and interconversion of substituted tetrahydrofolates. Blakley, R. L. Benkovic, S. J. eds. Folate and Pterins 1:255-306 Wiley New York, NY. .
6. Shane, B. (1989) Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vitam. Horm. 45:263-335.[Medline]
7. Weissbach, H. & Taylor, R. T. (1970) Roles of vitamin B 12 and folic acid in methionine synthesis. Vitam. Horm. 28:415-440.[Medline]
8. Miller, J. W., Nadeau, M. R., Smith, J., Smith, D. & Selhub, J. (1994) Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine’s co-ordinate regulation of homocysteine metabolism. Biochem. J. 298:415-419.
9. Balaghi, M. & Wagner, C. (1993) DNA methylation in folate deficiency: use of CpG methylase. Biochem. Biophys. Res. Commun. 193:1184-1190.[Medline]
10. Jacob, R. A., Gretz, D. M., Taylor, P. C., James, S. J., Pogribny, I. P., Miller, B. J., Henning, S. M. & Swendseid, M. E. (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J. Nutr. 128:1204-1212.
11. Blount, B. C. & Ames, B. N. (1994) Analysis of uracil in DNA by gas chromatography-mass spectrometry. Anal. Biochem. 219:195-200.[Medline]
12. Blount, B,C., Mack, M. M., Wehr, C. M., MacGregor, J. T., Hiatt, R. A., Wang, G., Wickramasinghe, S. N., Everson, R. B. & Ames, B. N. (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc. Natl. Acad. Sci. USA 94:3290-3295.
13. Riggs, A. D. & Jones, P. A. (1983) 5-Methylcytosine, gene regulation, and cancer. Adv. Cancer. Res. 40:1-30.[Medline]
14. Razin, A. & Cedar, H. (1991) DNA methylation and gene expression. Microbiol. Rev. 55:451-458.
15. Counts, J. L. & Goodman, J. I. (1994) Hypomethylation of DNA: an epigenetic mechanism involved in tumor promotion. Mol. Carcinog. 11:185-188.[Medline]
16. Sibani, S., Melnyk, S., Pogribny, I. P., Wang, W., Hiou-Tim, F., Deng, L., Trasler, J., James, S. J. & Rozen, R. (2002) Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice. Carcinogenesis 23:61-65.
17. Kim, Y. I., Salomon, R. N., Graeme-Cook, F., Choi, S. W., Smith, D. E., Dallal, G. E. & Mason, J. B. (1996) Dietary folate protects against the development of macroscopic colonic neoplasms in a dose-responsive manner in rats. Gut 39:732-740.
18. Kim, Y. I., Pogribny, I. P., Basnakian, A. G., Miller, J. W., Selhub, J., James, S. J. & Mason, J. B. (1997) Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am. J. Clin. Nutr. 65:46-52.
19. Kim, Y. I., Christmas, J. K., Fleet, J. C., Cravo, M. L., Salomon, R. N., Smith, D., Ordovas, J., Selhub, J. & Mason, J. B. (1995) Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. Am. J. Clin. Nutr. 61:1083-1090.
20. Rampersaud, G. C., Kauwell, G. P., Hutson, A. D., Cerda, J. J. & Bailey, L. B. (2000) Genomic DNA methylation decreases in response to moderate folate depletion in elderly women. Am. J. Clin. Nutr. 72:998-1003.
21. De Cabo, S. F., Santos, J. & Fernandez-Piqueras, J. (1995) Molecular and cytological evidence of S-adenosyl-L-homocysteine as an innocuous undermethylating agent in vivo. Cytogenet. Cell Genet. 71:187-192.[Medline]
22. Yi, P., Melnyk, S., Pogribna, M., Pogribny, I. P., Hine, R. J. & James, S. J. (2000) Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J. Biol. Chem. 275:29318-29323.
23. Kim, Y. I., Shirwadkar, S., Choi, S. W., Puchyr, M., Wang, Y. & Mason, J. B. (2000) Effects of dietary folate on DNA strand breaks within mutation-prone exons of the p53 gene in rat colon. Gastroenterology 119:151-161.[Medline]
24. Jhaveri, M. S., Wagner, C. & Trepel, J. B. (2001) Impact of extracellular folate levels on global gene expression. Mol. Pharmacol. 60:1288-1295.
25. Shen, J. C., Rideout, W., III & Jones, P. (1992) High frequency mutagenesis by a DNA methyltransferase. Cell 71:1073-1080.[Medline]
26. Pogribny, I. P., Basnakian, A. G., Miller, B. J., Lopatina, N. G., Poirier, L. A. & James, S. J. (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res 55:1894-1901.
27. Hansen, R., Ellis, N. & Gartler, S. (1988) Demethylation of specific sites in the 5' region of the inactive X-linked human phosphoglycerate kinase gene correlates with the appearance of nuclease activity and gene expression. Mol. Cell Biol. 8:4692-4699.
28. Zingg, J. M., Shen, J. C., Yang, A. S., Rapoport, H. & Jones, P. A. (1996) Methylation inhibitors can increase the rate of cytosine deamination by (cytosine-5)-DNA methyltransferase. Nucleic Acids Res 24:3267-3275.
29. Bayline, S. B., Belinsky, S. A. & Herman, J. G. (2000) Aberrant methylation of gene promoters in cancer-concepts, misconcepts, and promise. J. Natl. Cancer Inst. 92:1460-1461.
30. Tsujiuchi, T., Tsutsumi, M., Sasaki, Y., Takahama, M. & Konishi, Y. (1999) Hypomethylation of CpG sites and c-myc gene overexpression in hepatocellular carcinomas, but not hyperplastic nodules, induced by a choline-deficient L-amino acid-defined diet in rats. Jpn. J. Cancer Res. 90:909-913.[Medline]
31. Pogribny, I. P., Miller, B. J. & James, S. J. (1997) Alterations in hepatic p53 gene methylation patterns during tumor progression with folate/methyl deficiency in the rat. Cancer Lett 115:31-38.[Medline]
32. Herman, J. G., Merlo, A., Mao, L., Lapidus, R. G., Issa, J. P., Davidson, N. E., Sidransky, D. & Baylin, S. B. (1995) Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55:4525-4530.
33. Schroeder, M. & Mass, M. J. (1997) CpG methylation inactivates the transcriptional activity of the promoter of the human p53 tumor suppressor gene. Biochem. Biophys. Res. Commun. 235:403-406.[Medline]
34. Hiltunen, M. O., Alhonen, L., Koistinaho, J., Myohanen, S., Paakkonen, M., Marin, S., Kosma, V. M. & Janne, J. (1997) Hypermethylation of the APC (adenomatous polyposis coli) gene promoter region in human colorectal carcinoma. Int. J. Cancer 70:644-648.[Medline]
35. Siegfried, Z., Eden, S., Mendelsohn, M., Feng, X., Tsuberi, B. Z. & Cedar, H. (1999) DNA methylation represses transcription in vivo. Nat. Genet. 22:203-206.[Medline]
36. Herman, J. G. & Baylin, S. B. (2000) Promoter-region hypermethylation and gene silencing in human cancer. Jones, P. A. Vogt, P. K. eds. DNA Methylation and Cancer 2000:35-54 Springer Berlin, Germany. .
37. Myohanen, S. K., Baylin, S. B. & Herman, J. G. (1998) Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. Cancer Res 58:591-593.
38. Baylin, S. B., Herman, J. G., Graff, J. R., Vertino, P. M. & Issa, J. P. (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res. 72:141-196.[Medline]
39. Branda, R. F. & Blickensderfer, D. B. (1993) Folate deficiency increases genetic damage caused by alkylating agents and 
-irradiation in Chinese hamster ovary cells. Cancer Res 53:5401-5408.
40. Lathrop-Stern, L., Selhub, J., Choi, S. W. & Mason, J. B. (2000) Genomic DNA strand breaks in peripheral leukocytes are correlated with RBC folate concentrations in human subjects. FASEB J 14:A294(abs.).
41. Duthie, S. J., Narayanan, S., Blum, S., Pirie, L. & Brand, G. M. (2000) Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells. Nutr. Cancer 37:245-251.[Medline]
42. Choi, S. W., Kim, Y. I., Weitzel, J. N. & Mason, J. B. (1998) Folate depletion impairs DNA excision repair in the colon of the rat. Gut 43:93-99.
43. Fenech, M., Aitken, C. & Rinaldi, J. (1998) Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19:1163-1171.
44. Mori, H., Sugie, S., Yoshimi, N., Hara, A. & Tanaka, T. (1999) Control of cell proliferation in cancer prevention. Mutat. Res. 428:291-298.[Medline]
45. James, S. J., Miller, B. J., Basnakian, A. G., Pogribny, I. P., Pogribna, M. & Muskhelishvili, L. (1997) Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. Carcinogenesis 18:287-293.
46. Nensey, Y. M., Arlow, F. L. & Majumdar, A.P.N. (1995) Aging increased responsiveness of colorectal mucosa to carcinogen stimulation and protective role of folic acid. Dig. Dis. Sci. 40:396-401.[Medline]
47. Biasco, G., Zannoni, U., Paganelli, G. M., Santucci, R., Gionchetti, P., Rivolta, G., Miniero, R., Pironi, L., Calabrese, C., Febo, G. D. & Miglioli, M. (1997) Folic acid supplementation and cell kinetics of rectal mucosa in patients with ulcerative colitis. Cancer Epidemiol. Biomark. Prev. 6:469-471.[Abstract]
48. Akoglu, B., Faust, D., Milovic, V. & Stein, J. (2001) Folate and chemoprevention of colorectal cancer: is 5-methyl-tetrahydrofolate an active antiproliferative agent in folate-treated colon-cancer cells?. Nutrition 17:652-653.[Medline]
49. Fournel, M., Sapieha, P., Beaulieu, N., Besterman, J. M. & MacLeod, A. R. (1999) Down-regulation of human DNA-(cytosine-5) methyltransferase induces cell cycle regulators p16(ink4A) and p21(WAF/Cip1) by distinct mechanisms. J. Biol. Chem. 274:24250-24256.
50. Baylin, S. B. & Herman, J. G. (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168-174.[Medline]
51. Ryan, B. M. & Weir, D. G. (2001) Relevance of folate metabolism in the pathogenesis of colorectal cancer. J. Lab. Clin. Med. 138:164-176.[Medline]
52. Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., Boers, G. J., den Heijer, M., Kluijtmans, L. A. & van den Heuvel, L. P. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat. Genet. 10:111-113.[Medline]
53. Levine, A. J., Siegmund, K. D., Ervin, C. M., Diep, A., Lee, E. R., Frankl, H. D. & Haile, R. W. (2000) The methylenetetrahydrofolate reductase 677C
T polymorphism and distal colorectal adenoma risk. Cancer Epidemiol. Biomark. Prev. 9:657-663.
54. Song, C., Xing, D., Tan, W., Wei, Q. & Lin, D. (2001) Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res 61:3272-3275.
55. Shen, H., Spitz, M. R., Wang, L. E., Hong, W. K. & Wei, Q. (2001) Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study. Cancer Epidemiol. Biomark. Prev. 10:397-401.
56. Gershoni-Baruch, R., Dagan, E., Israeli, D., Kasinetz, L., Kadouri, E. & Friedman, E. (2000) Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur. J. Cancer 36:2313-2316.
57. Bagley, P. J. & Selhub, J. (1998) A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc. Natl. Acad. Sci. USA 95:13217-13220.
58. Stern, L. L., Mason, J. B., Selhub, J. & Choi, S. W. (2000) Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol. Biomark. Prev. 9:849-853.
59. Friso, S., Choi, S. W., Girelli, D., Mason, J. B., Dolnikowski, G. G., Bagley, P. J., Olivieri, O., Jacques, P. F., Rosenberg, I. H., Corrocher, R. & Selhub, J. (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc. Natl. Acad. Sci. USA 99:5606-5611.
60. Choi, S. W. (1999) Vitamin B12 deficiency: a new risk factor for breast cancer?. Nutr. Rev 57:250-253.[Medline]
61. Kato, I., Dnistrian, A. M., Schwartz, M., Toniolo, P., Koenig, K., Shore, R. E., Akhmedkhanov, A., Zeleniuch-Jacquotte, A. & Riboli, E. (1999) Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. Br. J. Cancer 79:1917-1922.[Medline]
62. Weinstein, S. J., Ziegler, R. G., Selhub, J., Fears, T. R., Strickler, H. D., Brinton, L. A., Hamman, R. F., Levine, R. S., Mallin, K. & Stolley, P. D. (2001) Elevated serum homocysteine levels and increased risk of invasive cervical cancer in U. S. women. Cancer Causes Control 12:317-324.[Medline]
This article has been cited by other articles:
|
|
 |
|
  L. M. Dong, J. D. Potter, E. White, C. M. Ulrich, L. R. Cardon, and U. Peters Genetic Susceptibility to Cancer: The Role of Polymorphisms in Candidate Genes JAMA, May 28, 2008; 299(20): 2423 - 2436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A D. Smith, Y.-I. Kim, and H. Refsum Is folic acid good for everyone? Am. J. Clinical Nutrition, March 1, 2008; 87(3): 517 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Marsillach, N. Ferre, J. Camps, F. Riu, A. Rull, and J. Joven Moderately High Folic Acid Supplementation Exacerbates Experimentally Induced Liver Fibrosis in Rats Experimental Biology and Medicine, January 1, 2008; 233(1): 38 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Al-Ghnaniem, J. Peters, R. Foresti, N. Heaton, and M. Pufulete Methylation of estrogen receptor {alpha} and mutL homolog 1 in normal colonic mucosa: association with folate and vitamin B-12 status in subjects with and without colorectal neoplasia Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1064 - 1072. [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]
|
|
|
|
 |
|
 S. C. Larsson, E. Giovannucci, and A. Wolk Folate and Risk of Breast Cancer: A Meta-analysis J Natl Cancer Inst, January 3, 2007; 99(1): 64 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Melse-Boonstra, P. Verhoef, C. E West, J. A van Rhijn, R. B van Breemen, J. J. Lasaroms, S. D Garbis, M. B Katan, and F. J Kok A dual-isotope-labeling method of studying the bioavailability of hexaglutamyl folic acid relative to that of monoglutamyl folic acid in humans by using multiple orally administered low doses. Am. J. Clinical Nutrition, November 1, 2006; 84(5): 1128 - 1133. [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]
|
|
|
|
 |
|
 Z Attias, H Werner, and N Vaisman Folic acid and its metabolites modulate IGF-I receptor gene expression in colon cancer cells in a p53-dependent manner. Endocr. Relat. Cancer, June 1, 2006; 13(2): 571 - 581. [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]
|
|
|
|
|
|
R. Z Stolzenberg-Solomon, S.-C. Chang, M. F Leitzmann, K. A Johnson, C. Johnson, S. S Buys, R. N Hoover, and R. G Ziegler Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am. J. Clinical Nutrition, April 1, 2006; 83(4): 895 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jang, J. B. Mason, and S.-W. Choi Genetic and Epigenetic Interactions between Folate and Aging in Carcinogenesis J. Nutr., December 1, 2005; 135(12): 2967S - 2971S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ulrich Nutrigenetics in Cancer Research--Folate Metabolism and Colorectal Cancer J. Nutr., November 1, 2005; 135(11): 2698 - 2702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kotsopoulos, A. Medline, R. Renlund, K.-J. Sohn, R. Martin, S. W. Hwang, S. Lu, M. C. Archer, and Y.-I. Kim Effects of dietary folate on the development and progression of mammary tumors in rats Carcinogenesis, September 1, 2005; 26(9): 1603 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fenech, P. Baghurst, W. Luderer, J. Turner, S. Record, M. Ceppi, and S. Bonassi Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, {beta}-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instability--results from a dietary intake and micronucleus index survey in South Australia Carcinogenesis, May 1, 2005; 26(5): 991 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Stempak, K.-J. Sohn, E.-P. Chiang, B. Shane, and Y.-I. Kim Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model Carcinogenesis, May 1, 2005; 26(5): 981 - 990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-I. Kim Will mandatory folic acid fortification prevent or promote cancer? Am. J. Clinical Nutrition, November 1, 2004; 80(5): 1123 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. D. Davis and E. O. Uthus DNA Methylation, Cancer Susceptibility, and Nutrient Interactions Experimental Biology and Medicine, November 1, 2004; 229(10): 988 - 995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Giovannucci Alcohol, One-Carbon Metabolism, and Colorectal Cancer: Recent Insights from Molecular Studies J. Nutr., September 1, 2004; 134(9): 2475S - 2481S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Huycke and H. R. Gaskins Commensal Bacteria, Redox Stress, and Colorectal Cancer: Mechanisms and Models Experimental Biology and Medicine, July 1, 2004; 229(7): 586 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Roncales, M. Achon, F. Manzarbeitia, C. Maestro de las Casas, C. Ramirez, G. Varela-Moreiras, and J. Perez-Miguelsanz Folic Acid Supplementation for 4 Weeks Affects Liver Morphology in Aged Rats J. Nutr., May 1, 2004; 134(5): 1130 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
