An overview of epigenetics and chemoprevention

Abstract

It is now appreciated that both genetic alteration, e.g. mutations, and aberrant epigenetic changes, e.g. DNA methylation, cause cancer. Epigenetic dysregulation is potentially reversible which makes it attractive as targets for cancer prevention. Synthetic drugs targeting enzymes, e.g. DNA methyltransferase and histone deacetylase, that regulate epigenetic patterns are active in clinical settings. In addition, dietary factors have been suggested to have potential to reverse aberrant epigenetic patterns. Uncovering the human epigenome can lead us to better understand the dynamics of DNA methylation in disease progression which can further assist in cancer prevention.

Figure 1

Simplified diagram shows the epigenetic patterns in promoters of active and inactive genes, and epigenetic patterns of inactive genes affected by epigenetic therapy and/or dietary factors. (A) Promoters of active genes are often associated with unmethylated CpG sites (white circle), acetylation of histone (green cross), and methylation of lysine 4 on histone H3 (H3K4) (yellow hexagon), and are absence of a nucleosome (blue sphere). This configuration favors the access of proteins that activate transcription. (B) During carcinogenesis, CpG sites on the promoters of genes, frequently tumor suppressor genes, are methylated (red circle). MBD mediates transcriptional repression through binding to methylated CpG sites and interacting with HDAC and DNMT. In addition, promoters of inactive genes are associated with methylation of lysine 9 or 27 on histone H3 (H3K9 or H3K27) (red hexagon) and a nucleosome. This pattern renders the chromatin inaccessibility. [3, 11] (C) Epigenetic therapy and/or dietary factors decrease DNMT, HDAC, and MBD, and increase acetylation of histones and methyl mark on H3K4 in the promoters of inactive genes. The chromatin might become more accessible to the transcription factors which then activate transcription.

Figure 1

Simplified diagram shows the epigenetic patterns in promoters of active and inactive genes, and epigenetic patterns of inactive genes affected by epigenetic therapy and/or dietary factors. (A) Promoters of active genes are often associated with unmethylated CpG sites (white circle), acetylation of histone (green cross), and methylation of lysine 4 on histone H3 (H3K4) (yellow hexagon), and are absence of a nucleosome (blue sphere). This configuration favors the access of proteins that activate transcription. (B) During carcinogenesis, CpG sites on the promoters of genes, frequently tumor suppressor genes, are methylated (red circle). MBD mediates transcriptional repression through binding to methylated CpG sites and interacting with HDAC and DNMT. In addition, promoters of inactive genes are associated with methylation of lysine 9 or 27 on histone H3 (H3K9 or H3K27) (red hexagon) and a nucleosome. This pattern renders the chromatin inaccessibility. [3, 11] (C) Epigenetic therapy and/or dietary factors decrease DNMT, HDAC, and MBD, and increase acetylation of histones and methyl mark on H3K4 in the promoters of inactive genes. The chromatin might become more accessible to the transcription factors which then activate transcription.

Figure 2. Methylation of cytosine by DNMTs and inhibiting methylation with 5-Azacytidine

(A) Using S-adenosylmethionine as the methyl group (CH₃) donor, DNMTs catalyze the methylation of the 5 position of the cytosine ring. (B) 5-Azacytidine, a cytosine analogue, is a hypomethylation drug which can block this reaction by replacing cytosine and acts as a direct and irreversible inhibitor of DNMTs. [8]