Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics

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.     

Cancer chemoprevention by dietary polyphenols: Promising role for epigenetics

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.     

Epigenetic control using natural products and synthetic molecules

The term "epigenetics" is defined as "heritable changes in gene expression that occur without changes in DNA sequence". Recently, it has been revealed that DNA methylation and histone modifications such as acetylation, methylation and phosphorylation are epigenetic mechanisms according to this definition. In other words, these posttranslational modifications are important factors in determining when and where a gene will be expressed. To date, several enzymes that catalyze DNA or histone modifications have been identified, such as DNA methyltransferases and histone deacetylases. Inhibitors and activators of enzymes controlling epigenetic modifications are considered useful not only as tools for the elucidation of cellular and biological phenomena, but also as therapeutic agents, since disruption of the balance of epigenetic networks is known to cause some disease states such as cancer. In this review, we present natural products and synthetic molecules that inhibit or activate enzymes catalyzing DNA methylation or histone modifications, and discuss the potential of epigenetic therapy.     

Epigenetic mechanisms in anti-cancer actions of bioactive food components - the implications in cancer prevention

The hallmarks of carcinogenesis are aberrations in gene expression and protein function caused by both genetic and epigenetic modifications. Epigenetics refers to the changes in gene expression programming that alter the phenotype in the absence of a change in DNA sequence. Epigenetic modifications, which include amongst others DNA methylation, covalent modifications of histone tails and regulation by non-coding RNAs, play a significant role in normal development and genome stability. The changes are dynamic and serve as an adaptation mechanism to a wide variety of environmental and social factors including diet. A number of studies have provided evidence that some natural bioactive compounds found in food and herbs can modulate gene expression by targeting different elements of the epigenetic machinery. Nutrients that are components of one-carbon metabolism, such as folate, riboflavin, pyridoxine, cobalamin, choline, betaine and methionine, affect DNA methylation by regulating the levels of S-adenosyl-L-methionine, a methyl group donor, and S-adenosyl-L-homocysteine, which is an inhibitor of enzymes catalyzing the DNA methylation reaction. Other natural compounds target histone modifications and levels of non-coding RNAs such as vitamin D, which recruits histone acetylases, or resveratrol, which activates the deacetylase sirtuin and regulates oncogenic and tumour suppressor micro-RNAs. As epigenetic abnormalities have been shown to be both causative and contributing factors in different health conditions including cancer, natural compounds that are direct or indirect regulators of the epigenome constitute an excellent approach in cancer prevention and potentially in anti-cancer therapy.     

表观遗传修饰在胚胎发育过程中的调控作用研究进展

表观遗传修饰是生命现象中普遍存在的一类基因调控方式,对维持哺乳动物正常生命活动至关重要。表观遗传修饰方式主要包括DNA甲基化、组蛋白乙酰化和组蛋白甲基化修饰,通常协同调控基因表达,且易受到营养和外源物等多种环境因素的影响,在胚胎正常发育中扮演重要角色。胚胎时期表观遗传修饰异常可能诱导胚胎甚至成年后多种疾病的发生。本文重点从DNA甲基化、组蛋白乙酰化和组蛋白甲基化修饰方面,综述表观遗传修饰在基因调控、胚胎发育过程中的作用及其可能的临床意义。     

Targeting epigenetic mechanisms: potential of natural products in cancer chemoprevention

The term epigenetics is defined as heritable changes in gene expression patterns that occur without changes in DNA sequence. Epigenetic changes according to this definition are achieved by methylation of cytosine bases in the DNA and by histone modifications, such as acetylation, methylation or phosphorylation. These modifications play an important role in regulating gene expression and the existence of an epigenetic code which maintains these modifications even upon cell division has been underlined by many investigations. Targeting the enzymes which catalyze DNA methylation or histone modifications may be a possibility not only for cancer therapy but also for chemoprevention since disruption of epigenetic balance is known to cause diseases such as cancer. In this review, we want to present the key epigenetic targets. We highlight natural products that modulate these epigenetic mechanisms and show their potential for cancer chemoprevention.     

Environment, diet and CpG island methylation: epigenetic signals in gastrointestinal neoplasia.

The epithelial surfaces of the mammalian alimentary tract are characterised by very high rates of cell proliferation and DNA synthesis, and in humans they are highly susceptible to cancer. The role of somatic mutations as drivers of carcinogenesis in the alimentary tract is well established, but the importance of gene silencing by epigenetic mechanisms is increasingly recognised. Methylation of CpG islands is an important component of the epigenetic code that regulates gene expression during development and normal cellular differentiation, and a number of genes are well known to become abnormally methylated during the development of tumours of the oesophagus, stomach and colorectum. Aberrant patterns of DNA methylation develop as a result of pathological processes such as chronic inflammation, and in response to various dietary factors, including imbalances in the supply of methyl donors, particularly folates, and exposure to DNA methyltransferase inhibitors, which include polyphenols and possibly isothiocyanates from plant foods. However the importance of these environmental interactions in human health and disease remains to be established. Recent moves to modify the exposure of human populations to folate, by mandatory supplementation of cereal foods, emphasise the importance of understanding the susceptibility of the human epigenome to dietary and other environmental effects.     

肿瘤表观遗传与代谢研究进展

表观遗传学是研究在基因核苷酸序列不发生改变的情况下基因表达可遗传的变化的一门学科,是生命科学领域的热点学科。其中,基于表观遗传学的肿瘤治疗更是近年来研究的热点前沿。本文从DNA与RNA的甲基化（包括甲基化介导的基因表达调控）、组蛋白修饰（与调控基因的相互作用交流）、染色质重塑相关基因的表达调控、代谢重编程及基于表观遗传调控的肿瘤治疗等几个方面对近年来肿瘤表观遗传热点问题与相关重大进展进行总结和讨论,以期为肿瘤的基础研究和临床治疗提供一定的借鉴。     

Epigenetics and cancer: implications for drug discovery and safety assessment

It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment.     

Techniques used in studies of epigenome dysregulation due to aberrant DNA methylation: an emphasis on fetal-based adult diseases

Epigenetic changes are heritable modifications that do not involve alterations in the primary DNA sequence. They regulate crucial cellular functions such as genome stability, X-chromosome inactivation, and gene imprinting. Epidemiological and experimental observations now suggest that such changes may also explain the fetal basis of adult diseases such as cancer, obesity, diabetes, cardiovascular disorders, neurological diseases, and behavioral modifications. The main molecular events known to initiate and sustain epigenetic modifications are histone modification and DNA methylation. This review specifically focuses on existing and emerging technologies used in studying DNA methylation, which occurs primarily at CpG dinucleotides in the genome. These include standard exploratory tools used for global profiling of DNA methylation and targeted gene investigation: methylation sensitive restriction fingerprinting (MSRF), restriction landmark genomic scanning (RLGS), methylation CpG island amplification-representational difference analysis (MCA-RDA), differential methylation hybridization (DMH), and cDNA microarrays combined with treatment with demethylating agents and inhibitors of histone deacetylase. The basic operating principals, resource requirements, applications, and benefits and limitations of each methodology are discussed. Validation methodologies and functional assays needed to establish the role of a CpG-rich sequence in regulating the expression of a target or candidate gene are outlined. These include in silico database searches, methylation status studies (bisulfite genomic sequencing, COBRA, MS-PCR, MS-SSCP), gene expression studies, and promoter activity analyses. Our intention is to give readers a starting point for choosing methodologies and to suggest a workflow to follow during their investigations. We believe studies of epigenetic changes such as DNA methylation hold great promise in understanding the early origins of adult diseases and in advancing their diagnosis, prevention, and treatment.     

Epigenetics: relations to disease and laboratory findings

Epigenetics is a postmeiotic modification of gene expression that is independent of the primary DNA sequence. DNA methylation, methylated DNA binding proteins, and histone modification-related enzymes are associated with epigenetics. Abnormalities in DNA methylation of CpG islands which are important for gene expression control, affect gene expression, which may influence carcinogenesis, aging, and other diseases. Aberrant DNA methylation occurs with aging, inflammation, viral infection, and carcinogenesis. DNA methylation can be evaluated for molecular analysis for diagnosis of early cancer. It is also important for laboratory diagnosis by using classic and authentic laboratory tests because the tests can be affected by epigenetics-controlled gene expression. It is also related to the effectiveness of therapeutic agents affecting DNA methylation and histone deacetylation, and the strategy in search of genetic abnormality for epigenetic as well as genetic error.     

Epigenetic impact of dietary polyphenols in cancer chemoprevention: lifelong remodeling of our epigenomes

Cancer, as one of the non-communicable diseases, remains one of the leading causes of death around the world. Recently, epigenetic changes in DNA methylation patterns at CpG sites (epimutations) or deregulated chromatin states of tumor promoting genes and noncoding RNAs emerged as major governing factors in tumor progression and cancer drug sensitivity. Furthermore, various environmental factors such as nutrition, behavior, stress, and toxins remodel our epigenomes lifelong in a beneficial or detrimental way. Since epigenetic marks (epimutations) are reversible in contrast to genetic defects, chemopreventive nutritional polyphenols (soy, genistein, resveratrol, catechin, curcumin) are currently evaluated for their ability to reverse adverse epigenetic marks in cancer (stem) cells to attenuate tumorigenesis-progression, prevent metastasis or sensitize for drug sensitivity. Although polyphenols in fruit and vegetables may help to reduce the risk of cancer, few protective effects have been firmly established, presumably because of inappropriate timing or dosing of diet exposure or due to confounding factors such as smoking and alcohol. In this review will discuss the possible epigenetic contributions of dietary polyphenols in cancer chemoprevention.     

细胞色素P450酶的表观遗传学调控及研究进展

细胞色素P450（CYPs）家族是体内重要的药物代谢酶,其功能主要是代谢临床药物及外源性物质。长期以来,CYP450酶的个体间功能活性差异往往被认为是由基因多态性所导致。然而随着研究的日益深入,人们发现基因序列的改变并不能完全解释CYP450酶的个体间活性差异。表观遗传学作为研究DNA序列未发生变化而基因表达发生可遗传变异的学科,可作为重要研究手段进一步解释CYP450酶的个体差异。该学科主要研究内容包括DNA甲基化、组蛋白翻译后修饰和RNA编辑等。本文就各主要CYP450酶的表观遗传学调控研究进行综述并讨论其在药物代谢和临床应用中的意义。     

A new paradigm in toxicology and teratology: altering gene activity in the absence of DNA sequence variation

'Epigenetics' is a heritable phenomenon without change in primary DNA sequence. In recent years, this field has attracted much attention as more epigenetic controls of gene activities are being discovered. Such epigenetic controls ensue from an interplay of DNA methylation, histone modifications, and RNA-mediated pathways from non-coding RNAs, notably silencing RNA (siRNA) and microRNA (miRNA). Although epigenetic regulation is inherent to normal development and differentiation, this can be misdirected leading to a number of diseases including cancer. All the same, many of the processes can be reversed offering a hope for epigenetic therapies such as inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases, histone deacetylases, and RNAi therapeutics. 'In utero' or early life exposures to dietary and environmental exposures can have a profound effect on our epigenetic code, the so-called 'epigenome', resulting in birth defects and diseases developed later in life. Indeed, examples are accumulating in which environmental exposures can be attributed to epigenetic causes, an encouraging edge towards greater understanding of the contribution of epigenetic influences of environmental exposures. Routine analysis of epigenetic modifications as part of the mechanisms of action of environmental contaminants is in order. There is, however, an explosion of research in the field of epigenetics and to keep abreast of these developments could be a challenge. In this paper, we provide an overview of epigenetic mechanisms focusing on recent reviews and studies to serve as an entry point into the realm of 'environmental epigenetics'.     

DNA甲基化与药物效应的表观遗传药理学研究进展

除遗传多态性外,DNA序列的表观遗传修饰,也可造成基因表达水平的改变,从而影响个体对药物的反应,造成药物效应的个体差异。表观遗传药理学研究整个环境因素对药物的影响,为临床药物效应的个体差异提供了新的作用机制学说。DNA甲基化是表观遗传修饰的主要机制之一,本文综述了DNA甲基化对药物效应的影响及环境因素对DNA甲基化的影响。     

Pharmocoepigenetics: a new approach to predicting individual drug responses and targeting new drugs

Epigenetics is the study of heritable changes in genes and gene expression that do not involve DNA nucleotide sequences. Epigenetic modifications include DNA methylation, several forms of histone modifications, and microRNA expression. Because of its dynamic nature, epigenetics provides a link between the genome and the environment and fills the gap between DNA and proteins. Advances in epigenetics and epigenomics (the study of epigenetics on a genome-wide basis) have influenced pharmacology, leading to the development of a new specialty, pharmacoepigenetics, the study of the epigenetic basis for variations in drug response. Many genes encoding enzymes, drug transporters, nuclear receptors, and drug targets are under epigenetic control. This review describes the known epigenetic regulation of drug-metabolizing enzymes and other proteins that might affect drug response and compounds that modify the epigenetic status.