Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation.
DNA methylation and histone acetylation contribute to the transcriptional regulation of genes involved in apoptosis. We have demonstrated that docosahexaenoic acid (DHA, 22:6 n-3) and butyrate enhance colonocyte apoptosis. To determine if DHA and/or butyrate elevate apoptosis through epigenetic mechanisms thereby restoring the transcription of apoptosis-related genes, we examined global methylation; gene-specific promoter methylation of 24 apoptosis-related genes; transcription levels of Cideb, Dapk1, and Tnfrsf25; and global histone acetylation in the HCT-116 colon cancer cell line. Cells were treated with combinations of (50 µM) DHA or linoleic acid (18:2 n-6), (5 mM) butyrate or an inhibitor of DNA methyltransferases, and 5-aza-2'-deoxycytidine (5-Aza-dC, 2 µM). Among highly methylated genes, the combination of DHA and butyrate significantly reduced methylation of the proapoptotic Bcl2l11, Cideb, Dapk1, Ltbr, and Tnfrsf25 genes compared to untreated control cells. DHA treatment reduced the methylation of Cideb, Dapk1, and Tnfrsf25. These data suggest that the induction of apoptosis by DHA and butyrate is mediated, in part, through changes in the methylation state of apoptosis-related genes.
Department of Nutrition and Food Science, Faculty of Nutrition, Texas A&M University, College Station, TX 77843-2253, USA.
Youngmi
Y
Cho
Nancy D
ND
Turner
Laurie A
LA
Davidson
Robert S
RS
Chapkin
Raymond J
RJ
Carroll
Joanne R
JR
Lupton
D000107:Acetylation / Q000187:drug effects; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000072224:Bcl-2-Like Protein 11; D002087:Butyrates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D064550:Death-Associated Protein Kinases / Q000235:genetics; D000077209:Decitabine; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D045325:HCT116 Cells; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology; D053259:Lymphotoxin beta Receptor / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002087:Butyrates; C112511:CIDEB protein, human; D006657:Histones; C505697:LTBR protein, human; D053259:Lymphotoxin beta Receptor; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506033:TNFRSF25 protein, human; D004281:Docosahexaenoic Acids; D000077209:Decitabine; D019787:Linoleic Acid; D015254:DNA Modification Methylases; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D001374:Azacitidine
DNA methylation; apoptosis; butyrate; docosahexaenoic acid; epigenetics