5-Methylcytosine depletion during tumour development: An extension of the miscoding concept

Abstract

Perhaps the most ubiquitous aspect of tumours and the neoplastic cells of which they are composed is their loss of the ability to control cellular functions in a normal way. During the development of the malignant state, the neoplastic cell becomes increasingly refractory to both the internal and external stimulae which integrate its normal counterparts into functional tissues and organ systems. This lack of integration is associated with alterations in the expression of a host of gene products, including, for example, the ectopic biosynthesis of hormones (

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

“…It is also a cofactor in the production of S-adenosylmethionine, the primary methyl donor in the body (Cooper, 1983). The S-adenosylmethioninedependent methylation of specific DNA cytosine bases to form 5-methylcytosine has been shown to block gene expression, as well as the abnormal expression of proto-oncogenes (Nyce et al, 1983;Hoffman, 1984). Increases in the levels of messenger RNA for the proto-oncogenes c-fos, c-HA-ras, and c-myc have been found to be correlated with the loss of methylation in the liver of rats on a low methyl diet (Wainfan and Poirier, 1992).…”

Meat and cancer: meat as a component of a healthy diet

“…Tumour suppressor genes are inactivated by methylation of normally unmethylated sites. DNA hypomethylation due to a diet low in methyl donors (eg low in meat) may contribute to a loss of protooncogene expression (Nyce et al, 1983). Indeed, throughout the different stages of colonic neoplastic transformation genomic hypomethylation (Goelz et al, 1985) methylation of usually unmethylated sites (Makos et al, 1992) and abnormal elevated DNA methyl transferase activity (Issa et al, 1993) are described.…”

Carcinogenicity and haemoglobin synthesis induction by cytidine analogues

“…Its known toxicities include immunosuppression, teratogenicity, abortifacient activity and gastrointestinal toxicities, and its biological effects include an inhibition of cell growth and liver regeneration (Cihak, 1974;Hrodek & Vesely, 1971;Weiss et al, 1972;Cihak & Vesely, 1969), alteration of protein synthesis (Reichman & Penman, 1973), gene activation (Nyce et al, 1983), and alteration of the differentiation properties of cells (Constantinides et al, 1977(Constantinides et al, , 1978. Recent interest in this drug has centered both on its ability to alter gene activity, and thus its use as a probe in understanding gene regulation, and also on its clinical applications in the induction of otherwise silent genes in the treatment of humans with sickle cell anaemia (Charache et al, 1983), ,B+thalassemia (Ley et al, 1982) and its potential in the treatment of other heritable diseases.…”

“…Inhibitors of DNA methylation will often activate previously silent genes and this is the strongest single line of evidence implicating methylation in gene control. There have been several recent reviews of mammalian DNA methylation (Holliday, 1979;Riggs & Jones, 1983;Nyce et al,1983;Doefler, 1983;Razin et al, 1984;Jones, 1986), and considering all data, it appears that methylation of DNA cytosine is one among several mechanisms significant in the control of mammalian gene expression (Riggs & Jones, 1983;Doefler, 1983;Razin et al, 1984), perhaps functioning primarily as a locking mechanism for the stable maintenance of the transcriptionally silent state (Razin & Riggs, 1980). There has been speculation that DNA methylation changes may play some role in tumour initiation or progression (Holliday, 1979;Riggs & Jones, 1983;Nyce et al, 1983;Jones, 1986), and some experimental data are now available.…”

“…There have been several recent reviews of mammalian DNA methylation (Holliday, 1979;Riggs & Jones, 1983;Nyce et al,1983;Doefler, 1983;Razin et al, 1984;Jones, 1986), and considering all data, it appears that methylation of DNA cytosine is one among several mechanisms significant in the control of mammalian gene expression (Riggs & Jones, 1983;Doefler, 1983;Razin et al, 1984), perhaps functioning primarily as a locking mechanism for the stable maintenance of the transcriptionally silent state (Razin & Riggs, 1980). There has been speculation that DNA methylation changes may play some role in tumour initiation or progression (Holliday, 1979;Riggs & Jones, 1983;Nyce et al, 1983;Jones, 1986), and some experimental data are now available. Evidence that DNA methylation changes may be associated with tumorigenesis is as follows: (a) The DNA of tumour cells has often been found to be undermethylated compared to the DNA of normal cells (although exceptions have been found) (Lapeyre et al, 1981;Gama-Sosa et al, 1983;Goelz et al, 1985); the methylation patterns of some genes that are expressed in tumour cells have been found to be altered in association with increased gene expression (Feinberg & Vogelstein, 1983a, b;Cheah et al, 1984); (b) the DNA of tumour metastases is less-methylated than the DNA of primary tumours (Gama-Sosa et al, 1983); (c) the DNA of primary malignant tumours is less-methylated than the DNA of benign tumours (Gama-Sosa et al, 1983); transformed cells have been shown to have their metastatic properties altered by the potent inhibitor of DNA methylation, 5-azacytidine (Olsson & Forchammer, 1984;Trainer et al, 1985;Ormerod et al, 1986); (e) several carcinogens have been shown to cause demethylation (Boehm & Drahovsky., 1979Salas et al, 1979;Wilson & Jones, 1983); (f) 5-azacytidine, an inhibitor of DNA methylase, has been shown to be a carcinogen in some experimental animal studies …”