Methyl deficiency, DNA methylation, and cancer: Studies on the reversibility of the effects of a lipotrope-deficient diet☆☆☆

Disturbance of DNA methylation patterns in the early phase of hepatocarcinogenesis induced by a choline‐deficient L‐amino acid‐defined diet in rats

“…Although the elevated expression of the c-fos, c-myc and c-Ha-ras genes was returned to control levels after ending the methyl-deficient diet feeding, hypomethylation of specific sites in these genes was irreversible. (14,15) In the present study, methylation of CpG sites within the CpG island observed was sparse, not dense, and the methylation was not associated with gene repression. Therefore, gene-specific hyper-and hypomethylation changes might persist and accelerate until the development of HCC under the feeding of the CDAA diet in rats.…”

“…(28,29) Regional hypomethylation of growth-related genes such as c-fos, c-myc, and c-Ha-ras has also been detected in the livers of rats after short-term feeding with the CD diet. (14,15) Moreover, hypomethylation of the c-myc gene in rat HCC induced by the CDAA diet has been reported. (18) In contrast, site-specific hypermethylation of the p16 gene in pre-neoplastic lesions and tumors has been reported to occur from folate/ methyl deficiency in rat livers.…”

“…(14,15) The CDAA diet used in the present study is semi-synthetic, and provides stronger carcinogenic effects than the CD diet in rats. (16,17) The authors have previously reported the hypomethylation of c-myc in HCC resulting from the CDAA diet in rats.…”

“…(12,13) So far, hypomethylation of the c-fos, c-myc, and c-Ha-ras genes has been detected in the livers of rats fed with the CD diet. (14,15) The CDAA diet used in the present study is semi-synthetic, and provides stronger carcinogenic effects than the CD diet in rats. (16,17) The authors have previously reported the hypomethylation of c-myc in HCC resulting from the CDAA diet in rats.…”

Hot-spot mutations in the p53 gene of liver nodules induced in rats fed DL-ethionine with a methyl-deficient diet

“…In addition to being hepatocarcinogenic per se, methyl-deficient diets also act as strong co-carcinogens of hepatocarcinogenesis by chemical carcinogens (Newberne, 1986;Shinozuka et al, 1986), including ethionine (Shinozuka et al, 1978;Leopold et al, 1982;Tsujiuchi et al, 1995). This chemical hepatocarcinogen is of singular interest because, when fed to rats, it decreases the availability of methyl groups for transmethylation reactions, including methylation of nucleic acids, as in the case of methyl-deficient diets (Farber, 1963;Ghoshal et al, 1986;Poirier, 1986;Christman et al, 1993). This effect of ethionine stems from the fact that it blocks the sulphur activation of methionine, leading to depletion of the primary donor of methyl groups, S-adenosylmethionine, and to formation instead of S-adenosylethionine, a transethylating agent.…”