Epigenetic alterations in ultraviolet radiation-induced skin carcinogenesis: interaction of bioactive dietary components on epigenetic targets

Abstract

The importance of epigenetic alterations in the development of various diseases including the cancers has been realized. As epigenetic changes are reversible heritable changes, these can be utilized as an effective strategy for the prevention of cancers. DNA methylation is the most characterized epigenetic mechanism that can be inherited without changing the DNA sequence. Although limited available data suggest that silencing of tumor suppressor genes in ultraviolet (UV) radiation-exposed epidermis leads to photocarcinogenesis and is associated with a network of epigenetic modifications including alterations in DNA methylation, DNA methyltransferases and histone acetylations. Various bioactive dietary components have been shown to protect skin from UV radiation-induced skin tumors in animal models. The role of bioactive dietary components, such as, (-)-epicatechins from green tea and proanthocyanidins from grape seeds has been assessed in chemoprevention of UV-induced skin carcinogenesis and underlying epigenetic mechanism in vitro and in vivo animal models. These bioactive components have the ability to block UV-induced DNA hypermethylation and histone modifications in the skin required for the silencing of tumor suppressor genes (e.g. Cip1/p21, p16(INK4a) ). This information is of importance for understanding the role of epigenetic modulation in UV-induced skin tumor and the chemopreventive mechanism of bioactive dietary components.

Figure 1

This hypothetical model depicts the: (i) progression of a normal skin cell into a cancer cell following epigenetic alterations under the influence of UV radiation, and (ii) the chemopreventive mechanism or targets of bioactive dietary components. Left Panel, cells containing a relatively uniform epigenetic code. Middle Panel, aging and the associated exposures to UV radiation alter epigenetic information in epidermal cell subsets such that, epigenetic mosaicism develops in patches of epidermal cells that have subtly altered gene expression. Right Panel, the sum total of changes in some of these patches result in neoplastic transformation. Topical application or dietary supplementation of bioactive food components may block, inhibit or slow down the progressing epigenetic alterations in cells exposed to UV radiation.

Figure 2

This schematic diagram depicts the conversion of cytosine into 5-methyl cytosine by the action of methyltransferase (Mtase). In this process different DNA methyltransferase enzymes play roles, such as Dnmt1, which has a role in normal maintenance of DNA methylation process while Dnmt3a and Dnmt3b are called De novo methylation enzymes. The inhibitory effect of bioactive component on Dnmts activity will block or reduce the hypermethylation of DNA and thus will lead to the reversal of epigenetic alterations.