Cancer chemoprevention by dietary polyphenols: promising role for epigenetics

Abstract

Epigenetics refers to heritable changes that are not encoded in the DNA sequence itself, but play an important role in the control of gene expression. In mammals, epigenetic mechanisms include changes in DNA methylation, histone modifications and non-coding RNAs. Although epigenetic changes are heritable in somatic cells, these modifications are also potentially reversible, which makes them attractive and promising avenues for tailoring cancer preventive and therapeutic strategies. Burgeoning evidence in the last decade has provided unprecedented clues that diet and environmental factors directly influence epigenetic mechanisms in humans. Dietary polyphenols from green tea, turmeric, soybeans, broccoli and others have shown to possess multiple cell-regulatory activities within cancer cells. More recently, we have begun to understand that some of the dietary polyphenols may exert their chemopreventive effects in part by modulating various components of the epigenetic machinery in humans. In this article, we first discuss the contribution of diet and environmental factors on epigenetic alterations; subsequently, we provide a comprehensive review of literature on the role of various dietary polyphenols. In particular, we summarize the current knowledge on a large number of dietary agents and their effects on DNA methylation, histone modifications and regulation of expression of the non-coding miRNAs in various in vitro and in vivo models. We emphasize how increased understanding of the chemopreventive effects of dietary polyphenols on specific epigenetic alterations may provide unique and yet unexplored novel and highly effective chemopreventive strategies for reducing the health burden of cancer and other diseases in humans.

Figure 1. Epigenetic mechanisms involved in carcinogenesis

Carcinogenesis is a long-term process and both genetic and epigenetic factors contribute to cancer development. Epigenetic changes, such as DNA methylation, histone modifications and microRNAs are easily influenced by dietary and environmental factors. Dietary polyphenols can potentially impact all three epigenetic modifications, which in turn contributes towards their chemopreventive potential.

Figure 2. Illustration depicting major plants with evidence for epigenetic modifications

The figure illustrates photographs from major plants with demonstrated evidence for epigenetic alterations in cancer cells. The ‘active principles’ for each of the plants are shown within parenthesis. These images were borrowed from various websites for illustration purposes only.

Figure 3. Effects of dietary polyphenols on the DNA methylation and histone modifications

Simplified scheme demonstrates a number of epigenetic changes that occur during carcinogenesis. In cancers, tumor suppressor genes become “inactivated” (shown as red circles) while oncogenes are “activated” (green circles). Epigenetic gene expression regulation is a complex process and several key enzymes play crucial roles. DNA methyltransferase (DNMT) is responsible for transfer of methyl group to 5′-cytosine. Histone acetylases (HAT) and histone deacetylases (HDAC) are responsible for the acetylation and de-acetylation of lysine residues within histone tails, respectively. Because of these histone modifications, conformational changes in chromatin structure lead to changes in DNA accessibility for transcription regulators and polymerases. Polyphenols can impact these enzymes in specific ways induces reversibility of epigenetic dysregulation in cancer cells.

Figure 4. Effect of dietary polyphenols on microRNA (miRNA) expression

miRNA are transcribed in the nucleus into primary miRNA (pri-miRNA) which is further cleaved by Drosha into precursor miRNA (pre-miRNA). Pre-miRNA is exported from nucleus to the cytoplasm and further processed by Dicer into miRNA duplex. Single strand of miRNA duplex (also called mature miRNA) leads this complex to mRNA cleavage or translation repression, which is dependent on miRNA:mRNA complementarity. Dependent on various factors, miRNA can have either an oncogenic role (called onco-miRNAs) if the target mRNA is a tumor suppressor gene, or a tumor suppressive role (tumor-suppressor miRNAs) if the target molecule is an oncogene. Dietary polyphenols can impact expression level of miRNAs and participate in gene expression regulation.