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.
Intracellular folate homeostasis is essential for the 1-carbon transfer reactions necessary for DNA synthesis and biological methylation reactions in colonic epithelial cells. Perturbed 1-carbon transfer reactions resulting from folate depletion predispose normal colonic epithelial cells to neoplastic transformation while inhibiting the growth of colon cancer cells. Using an in vitro model of folate deficiency, we determined the effects of folate deficiency on the steady-state transcript levels of genes involved in intracellular folate metabolism and 1-carbon transfer reactions in HCT116 and Caco2 human colon adenocarcinoma cells. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring increased folate uptake and intracellular folate retention, the provision of metabolically more effective substrates for folate-dependent enzymes, and reduced folate hydrolysis and efflux. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring the preferential shuttling of the flux of 1-carbon units to the methionine cycle over the nucleotide synthesis pathway. In Caco2 cells, some adaptive responses in response to folate depletion were not as apparent as in HCT116 cells, and in some cases, the direction of change was counterintuitive. In Caco2 cells, the metabolic priority in response to folate depletion was to shuttle the available folate pools to the nucleotide biosynthesis pathway at the expense of biological methylation reactions. In both HCT116 and Caco2 cells, folate depletion was associated with the conservation of the existing pattern and extent of DNA methylation.
Hayashi
Inki
I
Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada, M5S 1A8.
Sohn
Kyoung-Jin
KJ
Stempak
Joanne M
JM
Croxford
Ruth
R
Kim
Young-In
YI
D001483:Base Sequence; D018938:Caco-2 Cells; D002244:Carbon / Q000378:metabolism; D002460:Cell Line; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D014158:Transcription, Genetic
D017931:DNA Primers; D002244:Carbon; D005492:Folic Acid