METHYL-GROUPS IN CARCINOGENESIS - EFFECTS ON DNA METHYLATION AND GENE-EXPRESSION

Lipotrope-deficient (methyl-deficient) diets cause fatty livers and in creased liver-cell turnover and promote carcinogenesis in rodents. In rats prolonged intake of methyl-deficient diets results in liver tumor development. The mechanisms responsible for the cancer-promoting and carcinogenic properties of this deficiency remain unclear. The results of the experiments described here lend support to the hypothesis that intake of such a diet, by causing depletion of S-adenosylmethionine p ools, results in DNA hypomethylation, which in turn leads to changes i n expression of genes that may have key roles in regulation of growth. In livers of rats fed a severely methyl-deficient diet (MDD), lowered pools of S-adenosylmethionine and hypomethylated DNA were observed wi thin 1 week. The extent of DNA hypomethylation increased when MDD was fed for longer periods. The decreases in overall levels of DNA methyla tion were accompanied by simultaneous alterations in gene expression, yielding patterns that closely resembled those reported to occur in li vers of animals exposed to cancer-promoting chemicals and in hepatomas . Northern blot analysis of polyadenylated RNAs from livers of rats fe d control or deficient diets showed that, after 1 week of MDD intake, there were large increases in levels of mRNAs for the c-myc and c-fos oncogenes, somewhat smaller increases in c-Ha-ras mRNA, and virtually no change in levels of c-Ki-ras mRNA. In contrast, mRNAs for epidermal growth factor receptor decreased significantly. The elevated levels o f expression of the c-myc, c-fos, and c-Ha-ras genes were accompanied by selective changes in patterns of methylation within the sequences s pecifying these genes. Changes in DNA methylation and in gene expressi on induced in livers of rats fed MDD for 1 month were gradually revers ed after restoration of an adequate diet. In hepatomas induced by prol onged dietary methyl deficiency, methylation patterns of c-Ki-ras and c-Ha-ras were abnormal. Although human diets are unlikely to be as sev erely methyl deficient as those used in these experiments, in some par ts of the world intake of diets that are low in methionine and choline and contaminated with mycotoxins, such as aflatoxin, are common. Even in industrialized nations, deficiencies of folic acid and vitamin B-1 2 are not uncommon and are exacerbated by some therapeutic agents and by substance abuse. Thus, it seems possible that interactions of diet and contaminants or drugs, by inducing changes in DNA methylation and aberrant gene expression, may contribute to cancer causation in humans .