title: DNA methylation and histone modifications of Wnt genes by genistein during colon cancer development.
abstract: This study aims to elucidate the epigenetic mechanisms by which genistein (GEN) maintains a normal level of WNT genes during colon cancer development. We have reported that soy protein isolate (SPI) and GEN repressed WNT signaling, correlating with the reduction of pre-neoplastic lesions in rat colon. We hypothesized that SPI and GEN induced epigenetic modifications on Sfrp2, Sfrp5 and Wnt5a genes, suppressing their gene expression induced by azoxymethane (AOM), a chemical carcinogen, to the similar level as that of pre-AOM period. We identified that in the post-AOM period, histone H3 acetylation (H3Ac) was downregulated by SPI and GEN at the promoter region of Sfrp2, Sfrp5 and Wnt5a, which paralleled with the reduced binding of RNA polymerase II. Nuclear level of histone deacetylase 3 was enhanced by SPI and GEN. The diets suppressed the trimethylation of histone H3 Lysine 9 (H3K9Me3) and the phosphorylation of histone H3 Serine 10 (H3S10P). Methylation of the specific region of Sfrp2, Sfrp5 and Wnt5a genes was increased by SPI and GEN, which was inversely correlated with the reduction of gene expression. Bisulfite sequencing further confirmed that dietary GEN induced DNA methylation at CpG island of the promoter region of Sfrp5. Importantly, this region includes a fragment that had decreased H3Ac. Here, we present a potential epigenetic mechanism by which dietary GEN controls the responses of WNT genes during carcinogen induction, which involves DNA methylation, histone modifications and their interactions at the regulatory region of gene.
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018899:CpG Islands / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D030262:Soybean Proteins / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D000071818:Wnt-5a Protein; D000099186:Histone Deacetylase 3; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D019833:Genistein; D006655:Histone Deacetylases; D006657:Histones; D008565:Membrane Proteins; D012319:RNA Polymerase II; D030262:Soybean Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D000099186:Histone Deacetylase 3; C503650:Sfrp2 protein, rat; D000094742:Secreted Frizzled-Related Proteins; C491837:Wnt5a protein, rat