title: Black raspberries demethylate Sfrp4, a WNT pathway antagonist, in rat esophageal squamous cell papilloma.
abstract: Aberrant methylation of DNA is a common event in the development of cancers, including squamous cell carcinoma (SCC) of the human esophagus. In the present study, we determined: (a) whether aberrant DNA methylation also occurs in the development of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus, a model of human esophageal SCC; and (b) if so, whether dietary black raspberries (BRBs) are capable of preventing this aberrant DNA methylation. A diet containing 5% BRBs inhibited the development of NMBA-induced tumors in the rat esophagus. This inhibition was associated with reduced mRNA levels of the DNA methyltransferases, Dnmt1 and Dnmt3b, in both dysplastic lesions and in papillomas of the esophagus. In addition, promoter methylation of Sfrp4, a WNT pathway antagonist, was significantly reduced by the berry diet, and this was associated with decreased nuclear localization of β-CATENIN and reduced expression of c-MYC protein in NMBA-treated esophagi. Decreased promoter methylation of Sfrp4 correlated with decreased expression of Dmnt3b and, ultimately, with increased Sfrp4 mRNA expression. This suggests that epigenetic alterations in NMBA-induced rat esophageal tumorigenesis recapitulate epigenetic events in human esophageal SCC, and that BRBs could be useful in preventing the aberrant DNA methylation involved in the development of human esophageal SCC. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin. ywhuang@mcw.edu.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Children's Hospital Boston, Boston, Massachusetts.
authors.forename: Fei
authors.initials: F
authors.lastname: Gu
authors.affiliation: Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Alan
authors.initials: A
authors.lastname: Dombkowski
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Stoner
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000178:diet therapy* / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000009:adverse effects / Q000031:analogs & derivatives*; D044127:Epigenesis, Genetic / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000178:diet therapy* / Q000235:genetics; D000077277:Esophageal Squamous Cell Carcinoma; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D010936:Plant Extracts / Q000008:administration & dosage* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051381:Rats; D065856:Rubus / Q000737:chemistry*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000097584:DNA Methyltransferase 3B; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D004128:Dimethylnitrosamine; D010936:Plant Extracts; D011518:Proto-Oncogene Proteins; D000097584:DNA Methyltransferase 3B; C498455:Sfrp4 protein, rat; D000094742:Secreted Frizzled-Related Proteins; C014707:nitrosobenzylmethylamine; C000619380:DNMT1 protein, human; C000619382:Dnmt1 protein, rat
keywords: DNA methylation; Sfrp4; WNT signaling; black raspberries; rat esophageal tumor