Dietary black raspberries modulate DNA methylation in dextran sodium sulfate (DSS)-induced ulcerative colitis. Carcinogenesis 2013 Dec;34(12):2842-50
Date
09/27/2013Pubmed ID
24067901Pubmed Central ID
PMC3845896DOI
10.1093/carcin/bgt310Scopus ID
2-s2.0-84888984717 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
UNLABELLED: Ulcerative colitis (UC) is characterized by chronic inflammation of the colon. During inflammation, NF-κB is increased in colonic epithelial cells and in immune cells, leading to increases in proinflammatory cytokines. These events then increase DNA methyltransferases (DNMTs), which silence a subset of tumor suppressor genes by promoter methylation. Negative regulators of the Wnt pathway are frequently methylated in UC, leading to dysregulation of the pathway and, potentially, to colorectal cancer. We determined if black raspberries (BRBs) influence promoter methylation of suppressors in the Wnt pathway in dextran sodium sulfate (DSS)-induced UC. C57BL/6J mice received 1% DSS and were fed either control or 5% BRB diets. Mice were euthanized on days 7, 14 and 28, and their colons, spleen and bone marrow were collected. Berries reduced ulceration at day 28. This was accompanied by decreased staining of macrophages and neutrophils and decreased NF-κB p65 nuclear localization in the colon at all time points. At day 7, BRBs demethylated the promoter of dkk3, leading to its increased messenger RNA (mRNA) expression in colon, spleen and bone marrow. β-Catenin nuclear localization, c-Myc staining as well as protein expression of DNMT3B, histone deacetylases 1 and 2 (HDAC1 and HDAC2) and methyl-binding domain 2 (MBD2) were all decreased in colon; mRNA expression of these four proteins was decreased in bone marrow cells by BRBs. These results suggest that BRBs suppress colonic ulceration by correcting promoter hypermethylation of suppressor genes in the colon, as well as in the spleen and bone marrow that systematically regulate inflammation.
SUMMARY: Our results suggest that dietary BRBs suppress colonic ulceration by correcting promoter hypermethylation of suppressor genes in the colon, as well as in the spleen and bone marrow that systematically regulate inflammation in DSS-induced UC.
Author List
Wang LS, Kuo CT, Stoner K, Yearsley M, Oshima K, Yu J, Huang TH, Rosenberg D, Peiffer D, Stoner G, Huang YWMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Bone Marrow
Colitis, Ulcerative
Colon
DNA (Cytosine-5-)-Methyltransferases
DNA Methylation
DNA-Binding Proteins
Dextran Sulfate
Fruit
Histone Deacetylase 1
Histone Deacetylase 2
Intercellular Signaling Peptides and Proteins
Male
Mice
Mice, Inbred C57BL
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myb
RNA, Messenger
Spleen
Wnt Signaling Pathway
