**2. Epigenetics and cancer**

The progression of cancer is driven not only by acquired genetic alterations but also epigenetic modifications [4]. Epigenetic changes have been reported during cancer development and are found in genes involved in cell differentiation, proliferation, and apoptosis [4, 5]. DNA methylation is the most extensively studied epigenetic mark which occurs on cytosines followed by guanine (CpG), in humans [4, 5]. Methylation of CpGs plays a crucial role in regulation of gene expression [5, 6], which is necessary for orchestrating key biological processes, such as cell cycle, differentiation, and genomic imprinting, where, DNA hypermethylation is found in repetitive genomic sequences to maintain these regions in a transcriptionally inactive chromatin state [4–6].

## *Diet-Epigenome Interactions: Epi-Drugs Modulating the Epigenetic Machinery during Cancer… DOI: http://dx.doi.org/10.5772/intechopen.95374*

Cancer cells exhibit a global DNA hypomethylation, which causes chromosome instability leading to various mutations, loss of imprinting, activation of transposable elements disturbances in the genome, eventually, to cancer progression [5, 6]. On the other hand, a DNA hypermethylation of specific promoter regions of tumor suppressor genes leads to loss of expression of specific genes affecting pathways involved in maintenance of cellular functions, including apoptosis, DNA repair, and cell cycle, [5, 6]. Several tumor suppressor genes are silenced by promoter hypermethylation in tumors. Epigenetically mediated silencing of cyclin-dependent kinase inhibitor 2A, which is crucial for control of cell cycle has been reported in several cancers [5–7]. In addition, DNA hypermethylation-dependent silencing have been associated with the pathways regulated by microRNAs [5–7].

In cancer cells, DNA methyltransferases (DNMTs) are able to maintain DNA methylation and to de novo-methylate DNA of tumour suppressor genes [5, 6]. Recently, a new group of enzymes that induce demethylation of the DNA was found, the ten-eleven translocation (TET) enzyme family, that plays crucial roles both in tumorigenesis [5–7]. These aberrant DNA methylations are not limited to cancer cells; abnormal DNMT expressions are also linked to various diseases including cardiovascular diseases, type 2 diabetes, obesity, depression, anxiety disorder, dementia, and autism [7–9].

Gene expression is modulated by interactions between DNA methylation, histone modification, and nucleosome positioning effecting chromatin structure. Chromatin remodellers, chromatin-associated proteins, and methyl DNA binding proteins are important for structural modification of chromatin (**Figure 1**) [10].

Eukaryotic nuclei has histone proteins facilitating the dense packing of DNA and thus playing an essential role in the dynamic accessibility of DNA for transcription factors. In humans, there are two major histone families: linker histone (LH) and the core histones. The dynamic structure of chromatin allows changes in gene regulation [7–10]. The N-termini of histone proteins contain multiple lysine residues that are accessible to covalent modifications such as acetylation, methylation, phosphorylation, glycosylation, thus allowing regulation of gene transcription (**Figures 2** and **3**) [11, 12]. Aberrant expression of histone methyltransferases (HMTs), and histone demethylases (HDMs) has also been associated with cancer development [8–12].

In addition, cell cycle regulation, DNA repair mechanisms, chromosomal integrity, cellular senescence, and transcriptional activity of tumour-associated proteins such as

### **Figure 1.**

*Gene expression is modulated by interactions between DNA methylation, histone modification, and nucleosome positioning effecting chromatin structure [10].*

### **Figure 2.**

*Epigenetic markers on histone tails and DNA strand. Various enzymes (E) are responsible for the generation of epigenetic modification including DNA methylation/demethylation, histone acetylation/deacetylation, histone methylation/demethylation, histone biotinylation, crotonylation, phosphorylation and glycosylation [11].*

**Figure 3.** *Epigenetic mechanisms [12].*

p53, nuclear factor kappa-lightchain- enhancer of activated B cells (NF-κB), and the FoxO family [10–14] rely on a stable cellular metabolic state. In majority of cancer cells genomic instability is found causing an increased vulnerability against DNA damaging agents [12–14]. Therefore, cancer cells might be more susceptible to exogenous compounds causing oxidative stress by production of reactive oxygen species than healthy tissues [13]. Oxidative stress plays an important role in epigenetic reprogramming of expression of tumour suppressor genes, cytokines, and oncogenes, thereby setting up a ground for carcinogenesis [13, 14].

Unlike genetic defects, epigenetic modifications are reversible and represent a promising field in therapeutic interventions [15]. Due to epigenetic aberrations occur in early stages of cancer, approaches in targeting the epigenome have been proposed as preventive and therapeutic strategies [15, 16], that aim to reverse cancer-associated epigenetic changes and restore normal gene expression. A synergistic combination of epigenetic modifying agents, including miRNAs, may provide a clinically important reversal of epigenomic cancer states.

It is known that the cause of cancer is a complex interplay mechanism of genetic and environmental factors. Dietary nutrient intake is an environmental factor and a marked variation in cancer development with the same dietary intake between individuals has been identified [17]. The effects of dietary phytochemicals on gene

*Diet-Epigenome Interactions: Epi-Drugs Modulating the Epigenetic Machinery during Cancer… DOI: http://dx.doi.org/10.5772/intechopen.95374*

expression and signaling pathways have been widely studied in cancer [17, 18]. The present review aims to clarify the basic knowledge about the vital role of nutritionrelated genes in cancer, focusing on the role of dietary phytochemicals as epigenetic modifiers in cancer, and summarizing the progress made in cancer chemoprevention with dietary phytochemicals.
