Studies on hypomethylation of liver DNA during early stages of chemical carcinogenesis in rat liver

Abstract

Our finding that the inhibitors of DNA methylation, 5-azacytidine, 5-azadeoxycytidine or adenosine dialdehyde, given after a carcinogen all potentiated initiation suggested that hypomethylation of DNA during repair synthesis of DNA might play a role in the initiation of the carcinogenic process. To examine this aspect further, we have asked the question, do the nodules which develop from initiated cells after promotion with 1% orotic acid exhibit an altered methylation pattern in their DNA? The methylation status of the DNA from nodules has been examined using the restriction endonucleases HpaII/MspI and HhaI which distinguish between methylated and unmethylated cytosines in their nucleotide recognition DNA 5'-CCGG and 5'-GCGC respectively. The proto-oncogenes, c-myc, c-fos and c-Ha-ras, in the DNA were primarily studied in this investigation because of their possible involvement in cell proliferation and/or in cell transformation and tumorigenesis. The results indicate that in the nodule DNA, c-myc and c-fos are hypomethylated in the sequence of CCGG while the c-Ha-ras shows hypomethylation in the alternating GCGC sequence. This methylation pattern seen in the nodule DNA is not found in the DNA of the non-nodular surrounding liver or liver tissue after exposure to promoter or carcinogen alone. It is also not found in the DNA of regenerating liver. It is particularly significant that the methylation patterns in the c-myc and c-Ha-ras regions are similar to those found in several cancer tissues. The results suggest that this methylation pattern is acquired early in the carcinogenic process and raises the question whether it has any bearing on the process.

Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression

“…SAM, as a methyl group donor, is an essential cofactor for a variety of MeTases, including DNA MeTases, a group of enzymes responsible for DNA methylation. DNA methylation status contributes to the control of the expression of a variety of genes, including several oncogenes (5)(6)(7)(8). DNA hypomethylation is thought to constitute an early event in some cancers (7) and has been associated with many types of tumor (5,6,9,10).…”

Epigenetics in Cancer: The Myelodysplastic Syndrome as a Model to Study Epigenetic Alterations as Diagnostic and Prognostic Biomarkers

“…Several evidences of oncogenes and tumor supressor genes DNA methylation indicated the importance of these epigenetics changes under expression control. DNA hypomethylation was directly related to the overexpression of Raf, c-Myc, c-Fos, c-H-Ras and c-K-ras oncogenes and tumor liver formation (Rao et al, 1989). Hypermethylation of tumor suppressor genes has also been demonstrated.…”

Epigenetic aspects of genotoxic and non‐genotoxic hepatocarcinogenesis: Studies in rodents

“…It has been shown that several genotoxic hepatocarcinogens (i.e., 1,2-dimethylhydrazine, N-nitrosodiethyamine, N-nitrosomorpholine) cause alterations in DNA methylation, in addition to exerting genotoxic effects [Rao et al, 1989;Münzel et al, 1991;Park et al, 2001]. Recently, it has been suggested that these epigenetic changes may play a leading causative role in carcinogenic process induced by genotoxic agents [Jaffe, 2003;Bombail et al, 2004;Karpinets and Foy, 2005].…”