Black raspberries protectively regulate methylation of Wnt pathway genes in precancerous colon tissue. Cancer Prev Res (Phila) 2013 Dec;6(12):1317-27
Date
10/17/2013Pubmed ID
24129635Pubmed Central ID
PMC3902171DOI
10.1158/1940-6207.CAPR-13-0077Scopus ID
2-s2.0-84890525359 (requires institutional sign-in at Scopus site) 47 CitationsAbstract
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.
Author List
Wang LS, Kuo CT, Huang TH, Yearsley M, Oshima K, Stoner GD, Yu J, Lechner JF, Huang YWMESH terms used to index this publication - Major topics in bold
AnimalsColitis, Ulcerative
Colon
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
DNA-Binding Proteins
Diet
Female
Fruit
Histone Deacetylase 1
Histone Deacetylase 2
Humans
Immunoenzyme Techniques
Interleukin-10
Mice
Mice, Knockout
Precancerous Conditions
Promoter Regions, Genetic
RNA, Messenger
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Rosaceae
Sequence Analysis, DNA
Wnt Signaling Pathway
