Histone H3 lysine 9 and H4 lysine 20 trimethylation and the expression of Suv4-20h2 and Suv-39h1 histone methyltransferases in hepatocarcinogenesis induced by methyl deficiency in rats.
The field of cancer epigenetics has received much attention in recent years. However, the relationship of cancer epigenetics with cancer etiology is not clear. Recent studies suggest the involvement of altered DNA methylation and histone modifications in the emergence of epigenetically reprogrammed cells with specific tumor-related phenotypes at premalignant stages of tumor development. In this study, we used a methyl-deficient model of rodent hepatocarcinogenesis to examine the roles of DNA, histone H3 lysine 9 and histone H4 lysine 20 methylation, and the level of the expression of Suv39h1 and Suv4-20h2 histone methyltransferases in the carcinogenic process. We demonstrated that the development of liver tumors was characterized by progressive demethylation of DNA repeats, decrease in histone H4 lysine 20 trimethylation, and a gradual decrease in the expression of Suv4-20h2 histone methyltransferase. A prominent increase in the trimethylation of histone H3 lysine 9 and in the expression of Suv39h1 histone methyltransferase was observed in preneoplastic nodules and liver tumors indicating the promotional role of these epigenetic alterations at later stages of carcinogenesis. The appearance of tumor-specific epigenetic alterations (demethylation of repetitive elements, loss of histone H4 lysine 20 trimethylation, altered expression of Suv4-20h2 and Suv39h1 histone methyltransferases) at preneoplastic stages of hepatocarcinogenesis provides experimental support for the epigenetic hypothesis of tumorigenesis that considers stress-induced epigenetic reprogramming of the cell as an important prerequisite to succeeding mutations.
National Center for Toxicological Research, Jefferson, AR 72078, National Cancer Institute, Bethesda, MD 20892 and University of Tennessee, Knoxville, TN 37996, USA. ipogribny@nctr.fda.gov
Igor P
IP
Pogribny
Sharon A
SA
Ross
Volodymyr P
VP
Tryndyak
Marta
M
Pogribna
Lionel A
LA
Poirier
Tatiana V
TV
Karpinets
D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000096:biosynthesis* / Q000737:chemistry; D009154:Mutation; D011496:Protein Methyltransferases; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000737:chemistry
D006657:Histones; C512118:Kmt5c protein, rat; D012097:Repressor Proteins; C498700:Suv39h1 protein, mouse; C512117:Suv39h1 protein, rat; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase