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Vol. 60, Issue 6, 1288-1295, December 2001
Department of Cell and Cancer Biology, National Cancer Institute,
Bethesda, Maryland (M.S.J., J.B.T.); and Department of Biochemistry,
Vanderbilt University School of Medicine, Nashville, Tennessee (C.W.)
Methylation of DNA is associated with gene silencing. DNA methylation
uses S-adenosylmethionine (SAM) as the methyl donor and
the formation of SAM requires a continuous supply of folate from the
extracellular milieu. Low extracellular folate levels are known to
result in induction of expression of the human
folate receptor in
nasopharyngeal epidermoid carcinoma cells. Low folate levels have been
implicated in global activation of gene expression. We have
investigated the impact of lowering the level of extracellular folate
by performing cDNA microarray analysis of global gene expression in
human nasopharyngeal carcinoma KB cells grown in folate-deplete and
folate-replete medium. We found that expression of only eight genes
reproducibly responded to variation of folate levels. Among those,
three were up-regulated and five were down-regulated. Examination of
one gene, H-cadherin, demonstrated down-regulation in response
to folate depletion. Despite the low level of extracellular folate,
there was hypermethylation of H-cadherin 5' sequences. These data
indicate that low extracellular folate positively and negatively
influences the expression levels of a small cohort of genes. The data
suggest that folate deficiency is associated with gene-specific
methylation/demethylation, rather than global DNA demethylation and
transcriptional activation.
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