Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention

Abstract

The growing interest in cancer epigenetics is largely due to the reversible nature of epigenetic changes which tend to alter during the course of carcinogenesis. Major epigenetic changes including DNA methylation, chromatin modifications and miRNA regulation play important roles in tumorigenic process. There are several epigenetically active synthetic molecules such as DNA methyltransferase (DNMTs) and histone deacetylases (HDACs) inhibitors, which are either approved or, are under clinical trials for the treatment of various cancers. However, most of the synthetic inhibitors have shown adverse side effects, narrow in their specificity and also expensive. Hence, bioactive phytochemicals, which are widely available with lesser toxic effects, have been tested for their role in epigenetic modulatory activities in gene regulation for cancer prevention and therapy. Encouragingly, many bioactive phytochemicals potentially altered the expression of key tumor suppressor genes, tumor promoter genes and oncogenes through modulation of DNA methylation and chromatin modification in cancer. These bioactive phytochemicals either alone or in combination with other phytochemicals showed promising results against various cancers. Here, we summarize and discuss the role of some commonly investigated phytochemicals and their epigenetic targets that are of particular interest in cancer prevention and cancer therapy.

Keywords: Cancer; DNA methylation; Epigenetics; Histone deacetylation; Phytochemicals.

Figure 1

Effects of bioactive phytochemicals on promoter methylation and gene regulations. Dietary phytochemicals inhibit DNMTs and induce active demethylation at CpG-rich gene promoters. The transcription activation complex (TAC), which contains HATs, in general, binds to the unmethylated gene promoter leads to silencing of oncogenes and upregulation of tumor suppressor genes. When the gene promoter is methylated by DNMTs, the TAC becomes unable to bind to the gene promoter and initiation of transcription is inhibited. The transcription repression complex (TRC) containing HDACs is recruited to the methylated DNA which in general, leads to silencing of the tumor suppressor genes. Further, the bioactive dietary supplements also directly destabilize different epigenetic remodelling complexes such as TAC and TRC to prevent their binding with respective promoter regions for gene activation/ repression. The dietary phytochemicals-mediated upregulation of tumor suppressor genes and down regulations of oncogenes are the central importance of cancer prevention and therapy. M, methyl group.

Figure 2

Effect of bioactive dietary HAT and HDAC inhibitors on histone acetylation. HATs acetylate the lysine residues present in the histone tails thereby leading to formation of euchromatin state. This conformational change results in the binding of transcriptional activator complexes. The HDACs, in addition to deacetylation of these lysine residues, recruit transcriptional repressor complexes to the heterochromatin leading to gene silencing. The dietary HDAC inhibitors induce the expression of tumor suppressor genes and down regulation of oncogenes leading into suppression of carcinogenesis. A, acetyl group.