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Methyl groups in carcinogenesis: effects on DNA methylation and gene expression
1New York Blood Center, New York 10021.
Cancer Research
|April 1, 1992
Summary
Methyl-deficient diets cause fatty livers and promote cancer in rats by depleting S-adenosylmethionine, leading to DNA hypomethylation and altered gene expression. These changes are reversible, but abnormal patterns persist in tumors, suggesting dietary factors may contribute to human cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Lipotrope-deficient (methyl-deficient) diets induce fatty liver and promote carcinogenesis in rodents.
- Prolonged methyl-deficient diet intake in rats leads to liver tumor development.
- Mechanisms underlying the cancer-promoting effects of methyl deficiency are not fully understood.
Purpose of the Study:
- To investigate the hypothesis that methyl deficiency leads to S-adenosylmethionine depletion, DNA hypomethylation, and altered gene expression.
- To examine the impact of methyl-deficient diets on gene expression patterns related to cell growth and cancer.
- To assess the reversibility of these molecular changes upon dietary restoration.
Main Methods:
- Feeding rats a severely methyl-deficient diet (MDD) for varying durations.
- Measuring S-adenosylmethionine levels and DNA methylation status in liver tissues.
- Analyzing gene expression using Northern blot analysis for oncogenes (c-myc, c-fos, c-Ha-ras, c-Ki-ras) and growth factor receptors.
- Examining DNA methylation patterns within specific gene sequences.
Main Results:
- Within 1 week of MDD intake, rats showed depleted S-adenosylmethionine pools and hypomethylated DNA, with hypomethylation increasing over time.
- MDD induced significant increases in c-myc, c-fos, and c-Ha-ras mRNA levels, while epidermal growth factor receptor mRNA decreased.
- Selective changes in DNA methylation patterns within oncogene sequences accompanied the altered gene expression.
- Molecular changes were gradually reversed after restoring an adequate diet, but abnormal methylation patterns were observed in diet-induced hepatomas.
Conclusions:
- Methyl-deficient diets induce DNA hypomethylation and aberrant gene expression, potentially contributing to liver carcinogenesis.
- Dietary factors, contaminants, or drugs that alter DNA methylation may play a role in human cancer development.
- Understanding these molecular mechanisms is crucial for cancer prevention and therapeutic strategies.