title: Black raspberries protectively regulate methylation of Wnt pathway genes in precancerous colon tissue.
abstract: Ulcerative colitis is frequently an intermediate step to colon cancer. The interleukin-10 knockout mouse is a genetic model of this progression. We report that knockout mice fed 5% black raspberries (BRB) had significantly less colonic ulceration as compared with knockout mice that consumed the control diet. Dysfunction of the Wnt signaling pathway is a key event in ulcerative colitis-associated colon carcinogenesis. Therefore, we investigated the effects of BRBs on the Wnt pathway and found that the BRB-fed knockout mice exhibited a significantly lower level of β-catenin nuclear translocation. We followed-up this observation by evaluating the effect of BRBs on selected Wnt pathway antagonists. The mRNA expression levels of wif1, sox17, and qki were diminished in the knockout mice, whereas they were expressed at normal levels in knockout mice that were fed BRBs. The lower mRNA expression of these genes in the colon from the knockout mice correlated with hypermethylation of their promoter regions; BRBs decreased their promoter methylation and increased mRNA expression of these genes. This hypomethylation was associated with elevated protein expression of key proteins/enzymes that augment methylation, for example, dnmt3b, hdac1, hdac2, and mbd2 in the knockout mice; in addition, BRBs decreased the protein expression of these proteins/enzymes. The knockout mouse model recapitulates what occurs in human ulcerative colitis. Promoter methylation of CDH1 and SFRP1 was significantly higher in human ulcerative colitis tissues compared with their adjacent normal tissues. In conclusion, our results suggest that BRBs inhibit colonic ulceration and, ultimately, colon cancer partly through inhibiting aberrant epigenetic events that dysregulate Wnt signaling.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, TBRC, Room C4930, Milwaukee, WI 53226. liswang@mcw.edu.
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Wang
authors.forename: Chieh-Ti
authors.initials: CT
authors.lastname: Kuo
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.forename: Martha
authors.initials: M
authors.lastname: Yearsley
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Oshima
authors.forename: Gary D
authors.initials: GD
authors.lastname: Stoner
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: John F
authors.initials: JF
authors.lastname: Lechner
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004032:Diet; D005260:Female; D005638:Fruit / Q000737:chemistry*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D016753:Interleukin-10 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027824:Rosaceae / Q000737:chemistry*; D017422:Sequence Analysis, DNA; D060449:Wnt Signaling Pathway / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D016753:Interleukin-10; D012333:RNA, Messenger; D000097584:DNA Methyltransferase 3B; C489325:MBD2 protein, human; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human