Epigenetic Therapy Of Cancer

'Epigenetic' is a term used to describe a state of gene expression that is mitotically and meiotically inherited without any change in the sequence of DNA. Epigenetic mechanisms are mainly of two classes: (1) the DNA may be modified by the covalent attachment of a moiety that is then perpetuated. (2) a self-perpetuating protein state may be established (Zelent et al., 2004). The two most studied epigenetic phenomena are DNA methylation and histone tail modifications (Mai et al., 2005).

Methylation is the most commonly occurring epigenetic modification of human DNA. Under normal conditions, it helps to maintain transcriptional silence in non-expressed or non-coding regions of the genome. Methylation results from the activity of a family of DNA methyl transferases (DNMTs) that catalyze the addition of a methyl group to the 5-position (C5) of the cytosine ring, almost exclusively in the context of CpG dinucleotides. Low levels of DNA methylation in the promoter region of genes are linked to active gene expression. On the contrary, methylation near the transcription start site stand in the way of gene expression.

Apart from gene silencing, other effects of DNA methylation include spontaneous deamination, enhanced DNA binding of carcinogens and increased UV absorption by DNA, all of which increase the rate of mutations, DNA adduct formation and subsequent gene inactivation

DNA methylation is one such epigenetic phenomenon, which is abnormal in tumor cells (Szyf, 2003; Lund and van Lohuizen, 2004). Methylation of CpG islands, a feature of cancer cells, occurs rarely in normal tissue. Hence, methylation provides a tumor specific therapeutic target. De novo methylation as well as maintenance of methylation is carried out by DNMTs. There are 5 known human DNMTs - DNMT1, DNMT2, DNMT3a, DNMT3b and DNMT3L. Apart from DNMT2 and DNMT3L, which lack the amino terminal regulatory domain and the catalytic domain respectively (Goll and Bestor, 2005), the remaining DNMTs all have enzymatic function. Inactivation of DNMTs is the most effective means of inhibiting DNA methylation and restoring normal patterns of methylation. However, targeting the methyl transferase enzyme leads to loss of specificity and hypomethylation of the genome. The overall decrease in methylation level may even activate the potentially deleterious oncogenes (Szyf et al., 2004). DNA methylation inhibitors are of two broad classes: nucleoside and non-nucleoside analogues.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment