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Published on: August 25, 2015
Black raspberries demethylate Sfrp4, a WNT pathway antagonist, in rat esophageal squamous cell papilloma
Yi-Wen Huang1, Fei Gu2, Alan Dombkowski3
1Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin. ywhuang@mcw.edu.
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.
Insights
Dietary black raspberries (BRBs) prevent aberrant DNA methylation and tumor development in a rat model of esophageal squamous cell carcinoma (SCC). This suggests BRBs may offer a strategy for preventing human esophageal SCC.
Area of Science:
- Oncology
- Epigenetics
- Chemoprevention
Background:
- Aberrant DNA methylation is implicated in human esophageal squamous cell carcinoma (SCC) development.
- N-nitrosomethylbenzylamine (NMBA) induces esophageal tumorigenesis in rats, serving as a model for human SCC.
- Dietary interventions are being explored for cancer prevention strategies.
Purpose of the Study:
- To investigate aberrant DNA methylation in NMBA-induced rat esophageal tumorigenesis.
- To determine if dietary black raspberries (BRBs) can prevent this aberrant DNA methylation.
- To explore the molecular mechanisms underlying BRB chemoprevention.
Main Methods:
- Rats were administered NMBA to induce esophageal tumors, with some receiving a 5% BRB diet.
- mRNA levels of DNA methyltransferases (Dnmt1, Dnmt3b) were quantified.
- Promoter methylation of Sfrp4, a WNT pathway antagonist, was assessed.
- Nuclear localization of β-CATENIN and c-MYC protein expression were analyzed.
Main Results:
- BRB diet significantly inhibited NMBA-induced esophageal tumor development.
- BRBs reduced mRNA levels of Dnmt1 and Dnmt3b in dysplastic lesions and papillomas.
- Dietary BRBs decreased Sfrp4 promoter methylation, leading to reduced β-CATENIN and c-MYC.
- Reduced Sfrp4 methylation correlated with decreased Dnmt3b and increased Sfrp4 mRNA expression.
Conclusions:
- Epigenetic alterations in the NMBA-induced rat model mirror those in human esophageal SCC.
- Dietary black raspberries demonstrate chemopreventive potential against esophageal tumorigenesis.
- BRBs may prevent esophageal SCC by modulating aberrant DNA methylation and WNT pathway signaling.
