Epigenetic Modifications by Dietary Phytochemicals: Implications for Personalized Nutrition

Rakesh Sirvastava – In last two decades, the study of epigenetic modification emerged as one of the major areas of cancer treatment targeted by dietary phytochemicals. Recent studies with various types of cancers revealed that the epigenetic modifications are associated with the food source corresponds to dietary phytochemicals. The dietary phytochemicals have been used in Asian countries for thousands of years to cure several diseases including cancer. They have been reported to modulate the several biological processes including histone modification, DNA methylation and non-coding microRNA expression. These events play a vital role in carcinogenesis. Various studies suggest that a number of dietary compounds present in vegetables, spices and other herbal products have epigenetic targets in cancer cells. Dietary phytochemicals have been reported to repair DNA damage by enhancing histone acetylation that helps to restrain cell death, and also alter DNA methylation. These phytochemicals are able to modulate epigenetic modifications and their targets to cure several cancers. Epigenetic aberrations dynamically contribute to cancer pathogenesis. Given the individualized traits of epigenetic biomarkers, the personalized nutrition will help us to prevent various types of cancer. In this review, we will discuss the effect of dietary phytochemicals on genetic and epigenetic modifications and how these modifications help to prevent various types of cancers and improve health outcomes.

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Keywords: Epigenetics, Phytochemicals, DNA-methylation, Histone-modification, miRNA, Carcinogenesis.

1. Introduction

Dietary intervention experiments and epidemiological studies in humans using laboratory animals have provided evidence to suggest that lifestyle and environmental factors play a critical role in the development of a wide variety of neoplasms. Environmental factors including chemical carcinogens, environmental pollutants, dietary contaminants and physical carcinogens play important role in the etiology of human cancer (Kupchella CE 1986). Additionally, lifestyle factors, such as alcohol consumption, smoking, exposure to sunlight, increased fat consumption and chronic stress can also promote the development and progression of cancer (Stein CJ and Colditz GA 2004). It has further been demonstrated that maternal nutrition imbalance and metabolic disturbances during embryonic development have a persistent effect on the health of the offspring and may be passed down to the next generation (Attig L et al 2010). These studies provide evidence that cancer is a complex disease and manifestation of both genetic and epigenetic modifications (Macaluso M, Paggi MG et al. 2003). Cancer initiation and progression are primarily driven by acquired genetic alterations however microenvironment-mediated epigenetic perturbations play an important role in neoplastic development (Cho HS, Park JH et al. 2007). “Epigenetics” is defined as heritable changes in gene activity and expression that occur without alteration in DNA sequences and are sufficiently powerful to regulate the dynamics of gene expression (Goldberg AD, Allis CD et al. 2007; Stefanska B, Karlic H et al. 2012). Epigenetic modifications are potentially reversible, which makes them attractive and promising avenues for catering cancer preventive and therapeutic strategies. The key processes responsible for epigenetic regulation are DNA methylation, modifications in chromatin [covalent modification of core histones], and post-transcriptional gene regulation by non-coding RNA [micro-RNAs] (Dehan P, Kustermans G et al. 2009; Lim U and Song MA 2012). Additionally, some examples of genetic modifiers that alter epigenetic modifications are discussed in.

Table 1

Genetic Factors Which Control Epigenetic Modifications SrivastavaRakesh

S.No Gene Epigenetic Modifications Function Tumor Type Alteration References
1. ASXL Histone Modification Enhancer of trithorax and polycomb group (EAP) Additional sex combs like 1 Bohring-Opitz Syndrome, MDS and AML Mutation (Hoischen A, van Bon BW et al. 2011Gelsi-Boyer V, Brecqueville M et al. 2012)
2. BMI-1 Histone Modification PRC1 subunit Ovarian, mantle cell lymphomas and Merkel cell carcinomas Overexpression (Jiang L, Li J et al. 2009Lukacs RU, Memarzadeh S et al. 2010)
3. BRD4 Histone modification Bromodomain containing 4 Midline carcinoma, nuclear protein in testis, breast, colon, and AML Translocation (fusion protein), aberrant expression (Filippakopoulos P, Qi J et al. 2010Zuber J, Shi J et al. 2011)
4. CREBBP Histone Modification Histone acetyltransferase Colorectal, epithelial, gastric and ovarian, lung, esophageal cancer Mutation, overexpression (Miremadi A, Oestergaard MZ et al. 2007)
5. EP300 Histone Modification Histone deacetyltransferase Colorectal, breast, pancreatic cancer Mutation (Miremadi A, Oestergaard MZ et al. 2007)
6. EZH2 Histone Modification Histone methyltransferase H3K27 Colon, pancreas, liver, gastric, uterine tumors, breast, prostate, bladder, melanoma, lymphoma, myeloma, and Ewing’s sarcoma Mutation, aberrant expression (Chase A and Cross NC 2011Tsang DP and Cheng AS 2011)
7. G9a Histone Modification Histone methyltransferase H3K9 Cervical, uterine, HCC, ovarian, and breast cancer Aberrant expression (Varier RA and Timmers HT 2011)
8. HDAC2 Histone Modification Histone deacetyltransferase Gastric, Colonic, endometrial cancer Mutation (Ropero S, Fraga MF et al. 2006)
9. JARID1B/C Histone Modification Histone demethylase H3K4/H3K9 RCCC, testicular and breast, Overexpression (Rotili D 2011)
10. LSD1 Histone Modification Histone demethylase H3K4/H3K9 Prostate Mutation (Rotili D 2011)
11. MLL1/2/3 Histone modification Histone methyltransferase H3K4 Non-Hodgkin lymphoma, B cell lymphoma, Bladder TCC, ALL and AML, prostate (primary) Mutation, translocation, aberrant expression (Morin RD, Mendez-Lago M et al. 2011Yaoting Gui, Guangwu Guo et al. 2011)
12. PCAF Histone Modification Histone acetyltransferase Epithelial Mutation (Miremadi A, Oestergaard MZ et al. 2007)
13. PRMT1/5 Histone Modification Protein arginine methyltransferase Breast/gastric Aberrant expression (Miremadi A, Oestergaard MZ et al. 2007)
14. SIRT1, HDAC5/7A Histone modification Histone deacetyltransferase Colorectal, breast, prostate cancer Mutation, aberrant expression (Miremadi A, Oestergaard MZ et al. 2007)
15. UTX (KDM6A) Histone Modification Histone demethylase H3K27 Breast, kidney, lung, pancreas, bladder, esophagus, colon, uterus, brain Mutation (Rotili D 2011)
16. AID DNA methylation 5’cytidine deaminase CML Aberrant expression (De Carvalho DD, You JS et al. 2010)
17. DNMT1 DNA methylation DNA methyltransferase Pancreatic, gastric, breast, colorectal, non-small cell lung cancer Mutation, Overexpression (Kanai Y, Ushijima S et al. 2003Wu SC and Zhang Y 2010)
18. DNMT3A DNA methylation DNA methyltransferase MDS, AML Mutation (Ley TJ, Ding L et al. 2010Yamashita Y, Yuan J et al. 2010)
19. DNMT3B DNA methylation DNA methyltransferase ICF syndrome, SNPs in breast and lung adenoma Mutation (Wijmenga C, Hansen RS et al. 2000Shen H, Wang L et al. 2002)
20. IDH1/2 DNA methylation Isocitrate dehydrogenase Glioma, AML Mutation (Figueroa ME, Abdel-Wahab O et al. 2010Lu C, Ward PS et al. 2012)
21. MBD1/2 DNA methylation Methyl binding protein Breast and lung cancer Mutation (Sansom OJ, Maddison K et al. 2007)
22. TET1 DNA methylation 50methylcytosine hydroxylase AML Chromosome translocation (De Carvalho DD, You JS et al. 2010Wu SC and Zhang Y 2010)
23. TET2 DNA methylation 50methylcytosine hydroxylase Myeloid malignancies (AML), MDS, gliomas Mutation/silenc ing (Tan AY and Manley JL 2009)
24. ARID1A (BAF250A) Chromatin remodeling BAF subunit Carcinomas, endometrial carcinomas, ovarian clear cell carcinomas, 30% of endometrioid Mutation, genomic rearrangement, low expression (Jones S, Wang TL et al. 2010Guan B, Mao TL et al. 2011)
25. ARID2 (BAF200) Chromatin remodeling PBAF subunit Primary pancreatic adenocarcinomas Mutation (Li M, Zhao H et al. 2011)
26. BRD7 Chromatin remodeling PBAF subunit Bladder TCC Mutation (Drost J, Mantovani F et al. 2010)
27. BRG1(SMA CA4) Chromatin remodeling ATPase of BAF Lung, rhabdoid, medulloblastoma Mutation, low expression (Wilson BG and Roberts CW 2011)
28. BRM (SMARCA2) Chromatin remodeling ATPase of BAF Prostate, basal cell carcinoma Mutation, low expression (Sun A, Tawfik O et al. 2007de Zwaan SE and Haass NK 2010)
29. CHD4/5 Chromatin remodeling ATPase of NURD Gastric and colorectal cancer, ovarian, prostate, neuroblastoma Mutation (Bagchi A, Papazoglu C et al. 2007Kim MS, Chung NG et al. 2011Wang J, Wu Z et al. 2012)
30. CHD7 Chromatin remodeling ATP-dependent helicase Gastric and colorectal Mutation (Wessels K, Bohnhorst B et al. 2010)
31. P400/Tip60 Chromatin remodeling ATPase of SWR1, acetylase of SWR1 lymphomas, colon, head-and-neck, breast Mutation, aberrant expression (Mattera L, Escaffit F et al. 2009)
32. PBRM1 (BAF180) Chromatin remodeling PBAF subunit Breast tumor Mutation (Varela I, Tarpey P et al. 2011)
33. SNF5 (SMARCB1, INI1) Chromatin remodeling Gastric and colorectal Kidney malignant rhabdoid tumors, atypical rhabdoid/teratoid tumors (extra-renal), epithelioid sarcomas, small cell hepatoblastomas, extraskeletal myxoid chondrosarcomas, and undifferentiated sarcomas Mutation, silencing, loss of expression (Wilson BG and Roberts CW 2011)
34. SRCAP Chromatin remodeling ATPase of SWR1 Prostate Aberrant expression (Balakrishnan A, Bleeker FE et al. 2007)

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2. Histone modification

The histone modifications in chromatin structure play important role in the gene regulations and carcinogenesis (Sawan C and Herceg Z 2010). Chromatin proteins significantly involve in the packaging of eukaryotic DNA into higher order chromatin fibers. Each nucleosome consist of ~146 bp of DNA packed around an octamer of histone proteins, and the octamers mainly consist of double subunits of H2A, H2B, H3 and H4 core histone proteins. Histone proteins are regulators of chromatin dynamics either by providing protein recognition sites by specific modifications or changing chromatic structure by altering electrostatic charge (Mills AA 2010Suganuma T and Workman JL 2011). Histone modifications are specifically characterized by the genomic regulatory regions, for example inactive promoters which are enriched in trimethylated H3 at lysine 27 (H3K27me3) or trimethylated H3 at lysine 9 (H3K9me3), active promoter regions which are enriched in trimethylated H3 at lysine 4 (H3K4me3) and regulatory enhancers that are enriched in monomethylated H3 at lysine 4 (H3K4me1) and/or acetylated H3 at lysine 27 (H3K27ac) (Hon GC, Hawkins RD et al. 2009; Mills AA 2010; Hawkins RD, Hon GC et al. 2011). The histone proteins coordinate the changes between tightly packed DNA [heterochromatin] and exposed DNA [euchromatin] which are inaccessible to transcription and available for binding to and regulation of transcription factors respectively. These changes occur because of structural characteristics of the nucleosome that are known as ‘histone tails’, which extend from the core octamer. Histone tails are the major sites for posttranslational modifications which consist of Ntermini of the histone proteins. The two opposing group of enzymes (histone deacetylases (HDACs) and histone acetyltransferases (HATs)) involved in chromatin remodeling (Fig. 1). It has been reported that the dietary phytochemicals are involved in chromatin remodeling by acting on the enzymes HDACs and HATs (Hardy TM and Tollefsbol TO 2011). These enzymes are involved in genes deregulations which have been associated with the acetylation of histone proteins by HDACs and HATs. HATs catalyze histone acetylation by neutralizing the positive charge and facilitating the binding of transcription factors to nucleosomal DNA on the ε-amino groups of lysine residues in the N-terminal tails of core histones. On the contrary, HDACs catalyze deacetylation by cleavage of acetyl groups, typically producing a compact chromatin configuration that restricts transcription factor access to DNA and repressing gene expression. HDACs and HATs encompass a large group of enzymes which are classified into several families and control various physiological functions of the cells (Sawan C and Herceg Z 2010; Li Q and Chen H 2012).

Dietary Inhibitors of Histone Modifications

Figure shows the representation of histone modifications (acetylation and deacetylation) by the phytochemicals derived from different food source. Phytochemicals like EGCG, genistein and curcumin play important role in inhibition of histone acetylation by inactivating histone acetyl transferase enzyme. Some other phytochemicals like sulforaphane, curcumin, genistein, phenyl isothiocynate, organosulfur compound, resveratrol and indol-3-carbinol inhibits the deacetylation of relaxed chromatine by inactivating histone deacetylase enzyme. There are several other phytochemicals that alter histone modifications which are not covered in this figure.

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