Black Raspberries Protectively Regulate Methylation of Wnt Pathway Genes in Precancerous Colon Tissue
Menée sur un modèle murin, cette étude montre que la consommation de framboises noires peut prévenir la carcinogenèse du côlon par des mécanismes régulant la méthylation des gènes de la voie de signalisation Wnt dans les tissus pré-cancéreux
Ulcerative colitis (UC) is frequently an intermediate step to colon cancer. The interleukin-10 knock-out (KO) mouse is a genetic model of this progression. We report that KO mice fed 5% black raspberries (BRBs) had significantly less colonic ulceration as compared to KO mice that consumed the control diet. Dysfunction of the Wnt signaling pathway is a key event in UC-associated colon carcinogenesis. Therefore, we investigated the effects of BRBs on the Wnt pathway and found that the BRB-fed KO 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 KO mice, while they were expressed at normal levels in KO mice fed BRBs. The lower mRNA expression of these genes in colon from the KO 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, e.g., dnmt3b, hdac1, hdac2, and mbd2 in the KO mice; and BRBs decreased protein expression of these proteins/enzymes. The KO mouse model recapitulates what occurs in human UC. Promoter methylation of CDH1 and SFRP1 was significantly higher in human UC tissues compared to 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.