Epigenetic Impact of Dietary Polyphenols in Cancer

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Epigenetic impact of dietary polyphenols in

cancer chemoprevention: Lifelong remodeling
of our epigenomes
Article in Pharmacological Research March 2012
DOI: 10.1016/j.phrs.2012.03.007 Source: PubMed
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Pharmacological Research 65 (2012) 565576
Contents lists available at SciVerse ScienceDirect
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journal homepage: www.elsevier.com/locate/yphrs
Review
Epigenetic impact of dietary polyphenols in cancer chemoprevention:

Lifelong remodeling of our epigenomes
Wim Vanden Berghe a,b,
a
Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University Antwerp, Campus Drie Eiken, Universiteitsplein 1, Wilrijk,
Belgium
b
Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Physiology, Ghent University, K.L. Ledeganckstraat 35, Gent, Belgium
a r t i c l e
i n f o
Article history:
Received 10 February 2012
Received in revised form 10 March 2012
Accepted 13 March 2012
Keywords:
Cancer
Chemoprevention
Diet
Polyphenol
Epigenome
Epigenetics
a b s t r a c t
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 benecial 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 rmly 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.
2012 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chromatin states in the epigenomic cancer landscape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dietary chemoprevention of cancer-inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nutri-epigenomics: lifelong remodeling of our epigenomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epigenetic targets of bioactive dietary components for cancer prevention and therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Cancer remains a major health problem and is responsible for
one in eight deaths worldwide. Genome-wide association studies
have identied hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights
into their genetic architecture. Despite the success of genome-wide
association studies in identifying loci associated with cancer, a substantial proportion of the causality remains unexplained, leaving
Correspondence address: Laboratory of Protein Science, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University Antwerp,
Campus Drie Eiken, Universiteitsplein 1, Wilrijk, Belgium.
E-mail address: wim.vandenberghe@ua.ac.be
1043-6618/$ see front matter 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.phrs.2012.03.007
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many questions how the remaining missing heritability can be

explained, although polygenic disease traits may account for some
of this limitations [13]. Only a minority of cancers are caused by
germline mutations, whereas the vast majority (90%) are linked
to somatic mutations and environmental factors [4]. Also, an estimated 55% increase in cancer incidence is expected by the year 2020
[5]. A recent survey of the global incidence of cancer shows that the
age-adjusted cancer incidence in the Western world is above 300
cases per 100,000 population, whereas that in Asian countries is
less than 100 cases per 100,000. Observational studies have suggested that lifestyle risk factors such as tobacco, obesity, alcohol,
sedentary lifestyle, high-fat diet, radiation, and infections are major
contributors in cancer causes, which is further emphasized by the
increase in cancer cases among immigrants from Asian to Western
566
W. Vanden Berghe / Pharmacological Research 65 (2012) 565576
Fig. 1. Interplay of environmental oxidative stress, ROS, RNS, diet chemoprevention and epigenetics in Cancer. Oxidative damage of CpG motifs can result in cytosine
hydroxymethylation and formation of 8-oxoguanine, which may interfere with epigenetic dynamics in cancer biology, metastasis and drug sensitivity.
countries [4,6,7]. Reciprocally, a reasonable good fraction of cancer

deaths maybe prevented by modifying the diet composition (i.e.
content of ber, polyphenols, fat/oil, protein, spices, cereals, etc.)
and regular physical exercise [4,810]. Rather than the chemical
conversion of food to energy and body matter of classic metabolism,
food is now also a conditioning environment that shapes the activity of the (epi)genome and determines stress adaptative responses,
metabolism, immune homeostasis and the physiology of the body
[11,12]. The contribution of epigenetic changes (epimutations) to
human disease is probably underestimated. Epigenetics encompasses several extra-genetic processes such as DNA methylation
(methylation of cytosines within CpG dinucleotides), histone tail
modications (including acetylation, phosphorylation, methylation, sumoylation, ribosylation and ubiquitination), non-coding
RNA functions, regulation of polycomb group proteins and the epigenetic cofactor modiers, all of which may alter gene expression
but do not involve changes in the DNA sequence itself [1317]
(Fig. 1).
2. Chromatin states in the epigenomic cancer landscape
DNA methylation is the best-known epigenetic mark [18,19].
It is catalyzed by two types of DNMTs: DNMT1 is a maintenance methyltransferase, whereas both DNMT3A and DNMT3B are
de novo methyltransferases [20,21]. The role of DNMT2 in DNA
methylation is minor, its enzymology being largely directed to
tRNA. DNA methylation is normally associated with gene inactivation and it usually occurs in CpG dinucleotides. Alternatively,
DNA methylation of transcription factor binding sites which prevents binding of repressor proteins, may paradoxically induce
gene activation. CpGs are normally methylated when scattered
throughout the genome, but are mostly unmethylated when they
are clustered as CpG islands at 5 ends of many genes. Hypermethylation of CpG-rich promoters triggers local histone code
modications resulting in a cellular camouage mechanism that
sequesters gene promoters away from transcription factors and
results in stable silencing of gene expression. DNA methylation at
CpG dinucleotides occurs upon transfer of S-adenosylmethionine
(SAM) on cytosine by DNMTs. Whereas DNMT3A/B are responsible for DNA methylation during development (differentiation),
DNMT1 is in charge of maintaining DNA methylation patterns
in DNA replication during cell division. In mammalian cells, the
delity of maintenance of methylation is 9799.9% per mitosis,
whereas de novo methylation is as high as 35% per mitosis, thus
creating possibilities for epigenetic changes. Although in most cases
DNA methylation is a stable epigenetic mark, reduced levels of

methylation can also be observed during development. This net
loss of methylation can either occur passively by replication in
the absence of funtional maintenance methylation pathways, or
actively, by removing methylated cytosines. In mammals, coupling of 5-methylcytosine deaminase and thymine DNA glycosylase
activities maybe responsible for DNA demethylation. Alternatively, a role for the 5-hydroxymethylcytosine modication in
mammalian DNA demethylation has also been proposed as an
intermediate in an active DNA demethylation pathway involving
DNA repair and 5-hydroxymethylcytosine-specic DNA glycosylase activity [21]. Of particular interest, ROS and oxidative stress
may affect DNA demethylation by DNA oxidation or Tet mediated
hydroxymethylation [22,23].
In general, DNA is wrapped around nucleosomes, which are
arranged as regularly spaced beads (146 bp DNA/nucleosome)
along the DNA. Typically, nucleosomes consist of a histone octamer
of histones (H)2A/B, H3 and H4. The DNA bridging two adjacent
nucleosomes is normally bound by the linker histone H1 and is
termed linker DNA. While the core histones are bound relatively
tightly to DNA, chromatin is largely maintained by the dynamic
association with its architectural proteins. Before most activators
of a gene access their DNA-binding sites, a transition from a condensed heterochromatin (solenoid-like ber) to a decondensed
euchromatin (beads on a string) structure appears to take place.
Conversely, the acquisition of a more condensed heterochromatin
structure is often associated with gene silencing [15]. This structural restriction of silenced chromatin on gene expression can be
overcome by chromatin writer, reader and eraser enzyme complexes, which remodel nucleosomes along the DNA or reversibly
modify (acetylation, phosphorylation, ubiquitylation, glycosylation, sumoylation) histones on lysine, arginine, serine or threonine
residues of amino-terminal histone tails and establish specic chromatin states involved in transcription [15,24,25].
One critical facet of histone and DNA modifying enzymes
is that their activity also depends on intracellular levels of
essential metabolites (acetyl-coA, Fe, ketoglutarate, NAD+ , Sadenosylmethionine) of which the concentrations are tighly linked
to global cellular metabolism and energy levels [2631]. Gene
regulation is thus linked to the metabolic status of cells (Fig. 2).
To maintain uncontrolled cell proliferation of cancer cells, energy
metabolism needs to be adjusted in order to fuel cell growth and
vision. In contrast to healthy cells which mainly generate energy
from oxidative breakdown of pyruvate, cancer cell reprogram their
glucose metabolism, limiting their energy metabolism largely to
567
Fig. 2. Once critical facet of histone modications is that they are elicited by specic enzymatic activities that depend on the intracellular levels of essential metabolites:
these metabolites sense ROS, RNS, cellular metabolism, nutrients and energy levels in the cell. NAD, acetyl-coenzyme A (Acetyl-coA) and S-adenosylmethionine (SAM)
are elemental for epigenetic control of transcription including methylation of DNA and posttranslational modications of histones and non-histone chromatin factors (not
shown). NAD contributes to transcriptional control mainly via the activity of the protein deacetylase sirtuin (SIRT), which uses NAD as one of the substrates. Sirtuins are also
important for maintaining the activity of the acetyl-coA acetyltransferases. Ac-coA is synthesized by acetyl-coA-synthetase and ATP-citrate lyase that use acetate and citrate
as the precursor, respectively. Citrate is an intermediate/product of the TCA cycle. SAM is the methyl donor for DNA, RNA, histones and non-histone protein methylation.
SAH generated in each round of methylation reaction is a potent inhibitor of methyltransferases and has to be cleared by SAH hydrolase. NAD is an essential coenzyme for
SAHH. Synthesis of methionine from homocystein is achieved through extracting the methyl group from betaine, derived from choline, or 5-methyl-THF, a derivative of
folic acid. Metabolism of phospholipids and folic acid may thus indirectly contribute to epigenetic regulation. Likewise, the abundance of NAD and citrate is linked to the
cellular energy ux, e.g. the TCA cycle. Changes in the expression of certain genes may therefore be inuenced signicantly. Abbreviations used: Ac-coA, acetyl-coenzyme A;
ACS, acetyl-coA-synthetase; AC-ACS acetylated-ACS; Ado, adenosine; HAT, histone acetyltransferase; Hcy homocysteine; MTases, methyltransferases; NAD, Nicotinamide
adenine dinucleotide; ROS, reactive oxygen species; RNS, reactive nitrogen species; SAH, S-adenosyl homocysteine; TCA tricarboxylic cycle; THF, tetrahydrofolate.
glycolysis. The fundamental difference in ratio of glycolysis to mitochondrial respiration between normal and cancerous cells is also
known as the Warburg effect. As such, dynamic changes in energy
levels and metabolite concentrations in the inammatory tumor
microenvironment can have signicant epigenetic changes through
epigenetic cofactor enzymes [3237]. Specic sets of histone modications and/or variants are associated with genes that are actively
transcribed or are repressed, a phenomenon dened as the histone
code [15]. Based on coexisting histone marks and genomewide
ChIP-seq data available within the ENCODE consortium, principal component analysis allowed to reduce the complexity of the
histone code into 9 different chromatin states, linked to different
functional regulatory features [24,25].
The combinatorial nature of DNA methylation and histone modications signicantly extends the information potential of the
genetic cancer code [38]. The most studied epigenetic lesion, which
is DNA hypermethylation at the promoter region of many genes
[18,39], is proved to be responsible for silencing of more than 600
cancer-related genes and this number is still rising. They include
tumor suppressor genes, oncogenes as well as genes involved
in the cell-cycle regulation, DNA repair, angiogenesis, metastasis
and apoptosis [40]. Oxidative stress (ROS, RNS) and inammatory
damage play an important role in epigenetic reprogramming of
expression of cytokines, oncogenes and tumor suppressor genes,

thereby setting up a ground for chronic inammatory diseases and
carcinogenesis [4144]. On the other hand, global hypomethylation
of the DNA is said to activate endoparasitic sequences and causes
the global chromosome instability leading to various mutations and
cancer progression [45].
There is good evidence that also noncoding RNAs regulate chromatin architecture [16,4651]. The term non-coding RNA (ncRNA)
is commonly employed for RNA that does not encode a protein.
Although it has been generally assumed that most genetic information is transacted by proteins, recent evidence suggests that the
majority of the genomes of mammals and other complex organisms
is in fact transcribed into ncRNAs, many of which are alternatively spliced and/or processed into smaller products. Besides tRNA
and rRNA, these ncRNAs include long-noncodingRNAs (lncRNAs),
microRNAs (miRNAs) and tinyRNAs (tiRNAs) as well as several other classes of, sometimes yet-to-be-discovered [4648,51].
These RNAs (including those derived from introns) appear to
comprise a hidden layer of internal signals that control various levels of gene expression in physiology and development,
including chromatin architecture/epigenetic memory, transcription (enhancer function), RNA splicing, editing, translation and
turnover [16,17,5254]. RNA regulatory networks may determine
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Fig. 3. Dietary reversal of epigetic changes in cancer cells. Changes in DNA methylation have been recognized as one of the most common molecular alterations in human
neoplasia and hypermethylation of gene-promoter regions is being revealed as one of the most frequent mechanisms of loss of gene function. This gure summarizes how
changes in DNA-methylation (epimutations) contribute to the 6 hallmarks of a cancer cell, i.e. limitless replicative potential, self-sufciency in growth signals, insensitivity to
growth-inhibitory signals, evasion of programmed cell death, sustained angiogenesis and tissue invasion and metastasis. Since epigenetic changes (epimutations) are more
easily reversible (when compared with genetic mutations), this has inspired various research efforts aiming to identify dietary phytochemicals (nutri-epigenomics) which
can reverse epimutations and/or prevent cancer progression.
most of our complex characteristics and play a signicant role in

disease [52]. For example, miRNAs can change expression levels of
the epigenetic machinery (DNMT, HDAC, sirtuin (SIRT), polycomb
(Pc) proteins, etc.) by posttranscriptional gene regulation involving base pairing with 3 untranslated (UTR) regions in their target
mRNAs resulting in mRNA degradation or inhibition of translation
[16,53,5559]. Alternatively, long ncRNAs and tiRNAs can regulate
gene expression and/or DNA methylation by promoter association
[46,47,5052]. DNA-methylation can thus also be RNA-directed
[16,60].
Epigenetic defects in DNA methylation patterns at CpG sites
(epimutations), abnormalities in histone modications, chromatin
remodeling and noncoding RNAs (microRNA, long noncoding RNA)
or corrupt chromatin states of tumor suppressor genes or oncogenes recently emerged as major governing factors in tumor
progression and cancer drug sensitivity [14,1618,45,53,56,6163].
In addition, genetic mutations of epigenetic modifying enzymes
add another level of regulatory complexity [15,6468]. Recent
advances in genomic technologies have initiated large-scale
studies to map cancer-associated epigenetic variation, specifically variation in DNA methylation and chromatin states
[3,24,25,38,69,7072]. Given the prevalence of reversible epigenetic abnormalities in different cancers, epigenetic therapy holds
great promise for treatment. The future of specic and effective
epigenetic drug design will rely on our ability in understanding
epigenomic landscapes in normal and cancerous disease states
[7379].
3. Dietary chemoprevention of cancer-inammation
Cancer cells are distinguished by several distinct characteristics, such as self-sufciency in growth signal, resistance to growth
inhibition, limitless replicative potential, evasion of apoptosis,
sustained angiogenesis, and tissue invasion and metastasis [80]

(Fig. 3). Tumor cells acquire these properties due to cumulative
epigenetic changes of multiple genes and associated cell signaling pathways, most of which are linked to inammation. Immune
cells also inltrate in tumors, engage in an extensive and dynamic
crosstalk with cancer cells [42,81,82]. Inammation also affects
immune surveillance and responses to therapy [8386]. For that
reason, rationally designed drugs that target a single gene product
are unlikely to be of use in preventing or treating cancer. Moreover, targeted drugs can cause serious and even life-threatening
side effects or therapy resistance [80]. When a complex system
starts to dysfunction, it is generally best to x it early. Often,
cancers have a long latency period often 20 years or more. By
the time they are clinically detectable, the system has degenerated into a disorganized, chaotic mess at which point it may be
beyond repair [87]. Therefore, there is an urgent need for safe
and effective chemopreventive multifunctional drugs that act at
entire networks in the body, rather than single targets [88]. The
basic idea of cancer chemoprevention is to arrest or reverse the
progression of premalignant cells toward full malignancy using
physiological mechanisms that do not kill healthy cells [4,43,89,90].
The global demand for more affordable therapeutics and concerns about sides effects of commonly used drugs has renewed
interest in phytochemicals and traditional medicines which allow
chronic use [9193]. Studies on a wide spectrum of plant secondary
metabolites extractable as natural products from fruits, vegetables, teas, spices, and traditional medicinal herbs have identied
various bioactive polyphenols (genistein and soy polyphenols,
resveratrol, green tea polyphenols, curcumin, coffee polyphenols,
apple polyphenols), that regulate multiple cancer-inammation
pathways and epigenetic cofactors, are cost effective, exhibit low
toxicity, and are readily available [9496]. The recent advances
in genomics and metabolomics have enabled biologists to better
569
Fig. 4. Dietary modulation of transcription factor pathways which regulate chromatin oscillation dynamics between euchromatic and heterochromatic states at oncogenes
and tumor suppressor genes.
Fig. 5. Development of functional foods or dietary supplements as nutrition based epigenetic modulators of chromatin writers, readers and erasers in cancer chemoprevention. HAT, histone acetyltransferase; HDAC, histone deacetylase; DNMT, DNA methyltransferase; KMT, lysine methyltransferase; KDM, lysine demethylase; Me-CpG,
Methylcytosine; R, transcription repressor; A, Transcription activator; Ac, acety; Me, methyl.
570
investigate the potential use of immunomodulatory natural products for treatment or control of cancerous diseases. More recently,
evidence is emerging that specic combinations of polyphenols
maybe far more effective in protecting against cancer than isolated
compounds [92,97]. The cancer preventive or protective activities of the various immunomodulatory natural products lie in
their effects on cellular defenses including detoxifying and antioxidant enzyme systems, and the induction of anti-inammatory
and antitumor or antimetastasis responses, often by targeting
specic key transcription factors (i.e. like nuclear factor kappa B
(NFB), activator protein (AP-1), signal transducers and activators
of transcription (STAT3), nuclear factor erythroid 2-related factor (NRF2), peroxisome proliferator-activated receptor- (PPAR ),
estrogen receptor, liver X receptor (LXR), hypoxia inducible factor1 (HIF-1)), epigenetic cofactors as microRNAs which are involved
in tumor progression [59,98,99]. Typically, dysregulation of transcription factor activity is the result of numerous mechanisms,
such as changes in gene expression, proteinprotein interactions
and post-translational modications, leading to deregulation of
gene products that are involved in both inammation and carcinogenesis (Fig. 4). Remarkably, transient inammatory pathways
can trigger mitotic stable epigenetic switches from nontransformed to metastatic cancer cells via feedback signaling involving
NFB and STAT3 transcription factors, Lin28 and let-7 microRNAs
and the cytokine IL6 in the tumor microenvironment [100,101].
Similarly, emerging data demonstrate the direct inuence of certain anti-inammatory dietary factors (for example polyphenols,
isothiocyanates, epicatechins) and micronutrients (for example
folic acid, selenium) on heritable gene expression, activity of
the epigenetic machinery, DNA methylation, chromatin remodeling or microRNAs [11,102110] (Table 1). Because epigenetic
changes are reversible, developing drugs that control epigenetic
regulation now attracts substantial research investment, including
the development of functional foods or supplements as nutrition based epigenetic modulators for cancer chemoprevention
[10,12,59,92,111115] (Fig. 5). Sofar, it is not clear whether occasional consumption of polyphenols results in longterm epigenetic
regulation of gene expression and/or downstream chemopreventive effects.
4. Nutri-epigenomics: lifelong remodeling of our

epigenomes
Human epidemiological studies and appropriately designed
dietary interventions in animal models have provided considerable evidence to suggest that maternal nutritional imbalance and
metabolic disturbances, during critical time windows of development, may have a persistent effect on the health of offspring and
may even be transmitted to the next generation [102,116122].
This has led to the hypothesis of fetal programming and new
term developmental origin of health and disease (DOHaD): common disorders, such as cancer, obesity, cardiovascular disease
(CVD), diabetes, hypertension, asthma and even schizophrenia,
take root in early nutrition during gestation and continues during
lactation [90,102,123129]. Similarly, there is increasing evidence
in both plants and animals that nutritional intervention (caloric,
iron and protein restriction, polyphenol-, folate-, micronutrient-,
fat- or carbohydrate-rich diet), maternal diabetes, during pregnancy and lactation affects health in following generation(s)
[90,108,120,130133]. The various non-Mendelian features of
metabolic disease, cancer or chronic inammatory disorders, clinical differences between men and women or monozygotic twins and
uctuations in the course of the disease are consistent with epigenetic mechanisms in the inuence of fetal and/or lifelong nutrition
or stochastic events on adult phenotype [102,116121,134136].
Thus, lifetime shapes the multitude of epigenomes not only within,
but also across generations [102,117,120,125,137139]. Interest in
transgenerational epigenetic effects of food components has been
fueled by observations in Agouti mice fed with a soy polyphenol diet, which revealed epigenetic changes in DNA methylation
patterns in their offspring and protected against diabetes, obesity
and cancer across multiple generations [130,131,140]. Furthermore, maternal nutrient supplementation with soy polyphenols
was found to counteract xenobiotic-induced DNA hypomethylation
in early development [90,130,138,140142]. Other experiments
revealed the potential of polyphenols to inhibit the enzymatic
activity of human or bacterial DNMT in vitro in several studies
[143,144]. In silico DNMT docking studies revealed that polyphenols
may compete with cofactor SAM for binding to the catalytic pocket
Table 1
Polyphenols as epigenetic modulators in cancer chemoprevention.
Agent
Activity
Concentration
Refs.
Green tea/Cocoa
Catechins and
Polyphenols
Decrease DNMT activity in vitro

Decrease DNMT activity in vivo
Decrease DNA methylation in human
intervention study
Decrease H3K27 methylation
Decrease protein expression Bmi1, Suz12, Ezh2
Decrease DNMT activity
0.250 M
>7 cups/day
[109,143,150,224232]
520 M
2050 M
[146]
[109,233]
2 M
[147]
10 nM-100 M,
6 days
50250 mg/kg
[122,140,149,234247]
10100 mg/day 12
weeks
0.50100 M
[248251]
1 nM100 M
[145,252254]
Coffee polyphenols
Flavonoids and
polyphenols
Apple polyphenols
Genistein, soy
polyphenols
Resveratrol
Curcumin

Decrease DNMT expression/mRNA
Increase DNA methylation in vivo in rodents
Increase/Decrease DNA methylation in human
intervention studies
Decrease DNMT expression/mRNA
Increase/Decrease histone acetylation
Decreased HDAC6 expression
Decrease DNA methylation in human
intervention study
Decrease DNA methylation in cell lines
Increase activity SIRT1
Increase Sir2 yeast
Decrease p300, HDAC1, HDAC3
Decrease p300 HAT activity
of DNMT [145]. However, inhibition of DNMT maybe an indirect

consequence of methylation of the catechol moiety of polyphenols by catechol-O-methyltransferase (COMT) which competes for
the methyldonor pool available for DNA methylation [143,146].
Alternatively, polyphenols may change protein expression levels
of DNMT1, DNMT3B [147149]. In addition, treatment of cell culture models with tea polyphenols led to reduced genomic 5meC
levels and promoter hypomethylation of selected candidate genes
[146,150152]. Only very few epidemiological or human intervention studies with chemopreventive polyphenols have attempted
to investige effects on DNA methylation: despite the observation
of small changes in global DNA methylation related to diet, gender, age and sex, future longitudinal studies on bigger cohorts are
required to demonstrate its signicance and whether there is a
causal link between DNA methylation changes and disease progression [122,153156].
Recently, evidence emerged that also timing (preconception,
pregnancy, lactation, neonatal life, early life, pre-/post-menopause,
puberty) of various dietary exposures may be vitally important
in determining health benecial effects, as epigenetic plasticity
changes continually from conception to death [157,158]. If intervention with chemopreventive agents is started only after critical
events have taken place, a modulating effect would likely be
missed. For example epigenetic drugs prevented intestinal neoplasia in APCMin/+ mice by >95% when intervention was started
at the age of 1 week of age, whereas the compounds were ineffective when application started at 7 weeks of age [159]. Also
studies of human populations following famine have suggested
that pathologies in later life are dependent on the critical timing of nutritional insult during pregnancy [160162]. In principle;
epigenetic changes occurring during embryonic development will
have a much greater impact on the overall epigenetic status of
the organism because, as they can be transmitted over consecutive mitotic divisions, alterations occurring in single embryonic
stem cells will affect many more cells than those occurring in
adult stem and/or somatic cells during postnatal development
[119]. In addition to epigenetic imprinting during crucial periods of development, stochastic or genetically and environmentally
triggered epigenomic changes (epimutations) occur day after day
and accumulate over time, as maximal differences in DNA methylation proles are observed in aged monozygotic twins with a
history of non-shared environments [163,164]. Although it has long
been thought that the epigenomic prole is wiped clean in the
embryo shortly after fertilization, with the exception of imprinted
genes, methylation clearing is not complete after fertilization and
on a global DNA level is reduced to 10% [165,166]. Remarkably,
recent evidence suggests that DNA methylation is rather converted
into hydroxymethylation than erased [167170]. Alternatively, it
cannot be excluded that transgenerationally inherited nutritional
effects may also depend on polycomb proteins [120,137,171,172],
miRNA proles [16,173] or epigenetic capacitor properties of hsp
proteins present in the fertilized embryo [174176].
5. Epigenetic targets of bioactive dietary components for

cancer prevention and therapy
A next challenge will be to determine which adverse epigenomic
marks in cancer-inammation are reversible or can be prevented
by specic diets, natural phytochemicals or lifestyle changes
[102,108,117,157]. Numerous botanical species and plant parts
contain a diverse array of polyphenolic phytochemicals which exert
cancer chemopreventive effects in man by its anti-inammatory,
anti-oxidant, phytohormonal, homeostatic effects (hormesis) in
immune cells and/or cancer (stem)cells [89,113,177182]. Upon
re-exploration of its biological activities, various nutritional natural
571
compounds (including epigallocatechin gallate, resveratrol, genistein, curcumin, isothiocyanates, withanolides, . . .) were found to
interfere with enzymatic activity of DNMT, Class I, II, IV HDAC,
HAT and Class III HDAC sirtuins (SIRT) which modulate cancerinammation ([99,102111,127,183], and references included).
HDACs are zinc metalloproteins which rely on Zn2+ for their activity
and are divided into 4 classes based on their homology with yeast
HDACs. Class III HDACs, called sirtuins are zinc-independent but
nicotinamide adenine dicnucleotide (NAD+ )-dependent. Class I, II,
IV HDAC inhibitors characteristically contain a Zn2+ chelating group
consisting of a thiolate, thiol, hydroxamate, carboxylate, mercaptoamide, epoxide or ketone group. Natural HDAC inhibitors can be
divided in following groups based on their chemical characteristics:
carboxylates, organosuldes, isothiocyanates, hydroamates, cyclic
tetrapeptides and macrocyclic depsipeptides [105]. In contrast to
natural HDAC inhibitors, only few natural products (i.e. niacine,
vitamin B3, dihydrocoumarin) have been identied as inhibitors
of class III HDACs. Reciprocally, various natural avonoids have
been identied as activators of class III HDACs (SIRTs). Finally,
turmeric and green tea have been identied as sources of natural inhibitors of p300/CBP HAT. Finally DNMT inhibitors work
mainly through one of the following mechanisms, either covalent
trapping of DNMT through incorporation into DNA (i.e. nucleoside
analogs decitabine, 5-azacytidine), non-covalent blocking of DNMT
catalytic active site (i.e. EGCG, parthenolide), interruption of binding site of DNMT to DNA (i.e. procaine), degradation of DNMT (i.e.;
decitabine), or suppression of DNMT expression (i.e. miRNAs). Specic epigenetic effects of natural phytochemicals may be the result
of a superposition of combined concentration dependent actions of
the compound as a nuclear hormone receptor ligand and/or modulator of histone modifying enzymes and DNMTs [184188] which
may target chromatin dynamics of specic gene clusters. Although
effects of dietary factors and extracts have frequently been demonstrated in in vitro experiments at concentrations which can never
be achieved in vivo, epigenetics sheds a more realistic light on
dietary studies, as longlife exposure at physiological concentrations
can remodel the epigenome in a cumulative fashion by repetitive effects on the epigenetic machinery [189193]. Furthermore,
it should be evaluated which epigenetic changes are stable over
time. Interestingly, even transient exposure to a specic dietary
component can induce long-lasting epigenetic changes in the promoter of the NFB subunit p65, which acts as a master switch in
cancer-inammation [194]. Alternatively, compounds may chemically interfere with histone mark interacting effector domains
(such as chromo-, bromo- or tudor domains) [195197]. Though,
one should be careful with interpretation of in vitro compound
screenings or cofactor activity assays based on peptide-protein
interactions, which may not always represent true targets in vivo
[198,199].
From another perspective, chemopreventive phytochemicals
may indirectly modulate chromatin dynamics and epigenetic
effects upon interference with global cancer metabolism. As such,
epigenetic changes may follow biochemical metabolization of
dietary factors, which can deplete cellular pools of acetyl-CoA,
NAD+ and methyldonors, resulting in unbalanced DNA methylation
and/or protein acetylation or methylation [31,183,200]. For example, avanol-rich diets interfere with the methyldonor metabolism
and the available pool of S-adenosylmethionine, resulting in
changes in DNA methylation [201205] and histone methylation, which is also affected by alterations in SAM/SAH ratios
[206,207]. Furthermore, even without nutritional deciency of
methyl groups, impaired synthesis of SAM and perturbed DNA
methylation can happen when the need for the synthesis of
the detoxication enzyme glutathione transferase (GSH) synthesis increases [208]. Diets or nutritional compounds which affect
energy metabolism or mitochondrial respiration can have global
572
epigenetic effects upon changes in NAD+ availability and SIRT

activity [209]. Since SIRT activation has been linked to longevity
(increased lifespan and healthy aging) and mimics a caloric
restricted diet, SIRT activators such as resveratrol represent a major
class of caloric mimetic epigenetic modulator phytochemicals
which could reverse metabolic disease [200]. Along the same line,
avanol-rich diets interfere with the methyldonor metabolism and
the available pool of S-adenosylmethionine, resulting in changes in
DNA and histone methylation [202207]. As such, specic dietary
classes of functional food maybe designed as therapeutic epigenetic
modulators in cancer-inammation.
6. Conclusion and future perspectives

The phenotype of an individual is the result of complex
geneenvironment interactions in the current, past and ancestral
environment, leading to lifelong remodeling of our epigenomes.
In recent years, several studies have demonstrated that disruption of epigenetic mechanisms can alter immune function and
contribute to various cancers. Various replication-dependent and
-independent epigenetic mechanisms are involved in developmental programming, lifelong recording of environmental changes
and transmitting transgenerational effects. It is likely that understanding and manipulating the epigenome, a potentially reversible
source of biological variation, has great potential in chemoprevention or stabilization of cancer. Much attention is currently
focusing on modulating hyper/hypomethylation of key inammatory genes by dietary factors as an effective approach to cure or
protect against cancer-inammation [102110,127,183]. In this
respect, Let food be your epigenetic medicine could represent a
novel interpretation of what Hippocrates said already 25 centuries
ago. As such, it will be a challenge for future anti-inammatory
therapeutics and preventive cancer research to identify novel
epigenetic targets which allow selective modulation of the inammatory signaling network in the diseased tumor microenvironment
[89,96,210214]. Given several encouraging trials, prevention and
therapy of age- and lifestyle-related diseases by individualized
tailoring of optimal epigenetic diets or supplements are conceivable. However, these interventions will require intense efforts
to unravel the complexity of these epigenetic, genetic and environment interactions. Another goal is to evaluate their potential
reversibility with minimal side effects as diet components may
reprogram malignant cells as well as the host immune system
and HPA-axis depending on the bioavailability of the dietary
compounds [102,191,193,215217]. There is some concern that
epigenetic therapy with dietary inhibitors of DNMT, HDAC, histon(de)methylases in longterm treatment setups may suffer from
lack of specicity [184,195,198]. As such, the possible alternative is to combine nonselective epigenetic therapies with more
targeted approaches [218]. For example, combined treatment of
specic transcription factor inhibitors and/or hormone receptor
ligands with epigenetic drugs may trigger synergistic activities at
subsets of inammatory genes [218222]. An excellent example
of cooperation between a dietary vitamin A-derivative targeting
a nuclear receptor and the HDAC inhibitor butyrate has been
described in the treatment of acute promyelocytic leukemias [103].
Finally, microRNA and long ncRNA pathways also hold promise
to join soon the arsenal of epigenetic combination therapies, as
their target sequence specicity may bridge the gap between
genetic and epigenetic changes [16,5052,59]. As such, dietary
polyphenols may indirectly modulate the epigenome by miRNAs
which target specic epigenetic modier enzymes [54,223]. In
conclusion, cancer-inammaton studies are revealing a dazzling
complexity in the mechanisms leading to dynamic alterations of
the epigenome and the need of combination therapies targeting
different chromatin modiers, to reverse disease prone epigenetic

alterations for chemoprevention. Medical benets of dietary compounds as epigenetic modulators, especially with respect to their
chronic use as nutraceutical agents, will rely on our further understanding of their epigenetic effects during embryogenesis, early life,
aging, carcinogenesis as well as through different generations.
Acknowledgements
This research is partially nancial supported by FP7 grant FLAVIOLA (www.aviola.org), an NOI-grant (UA), a Research Grant from
the Multiple Myeloma Research Foundation (MMRF) and Interuniversity Attraction Poles (IAP) P6/18. We regret that all literature
could not be appropriately cited because of space constraints and
we apologize to those authors whose original work is not mentioned.
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Epigenetic Impact of Dietary Polyphenols in Cancer

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Epigenetic impact of dietary polyphenols in

Pharmacology of Natural Product / Neuroprotection View project

Pharmacological Research 65 (2012) 565576

Contents lists available at SciVerse ScienceDirect

Epigenetic impact of dietary polyphenols in cancer chemoprevention:

many questions how the remaining missing heritability can be

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

countries [4,6,7]. Reciprocally, a reasonable good fraction of cancer

DNA methylation is a stable epigenetic mark, reduced levels of

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

expression of cytokines, oncogenes and tumor suppressor genes,

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

most of our complex characteristics and play a signicant role in

sustained angiogenesis, and tissue invasion and metastasis [80]

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

4. Nutri-epigenomics: lifelong remodeling of our

Decrease DNMT activity in vitro

Decrease DNMT activity

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

of DNMT [145]. However, inhibition of DNMT maybe an indirect

5. Epigenetic targets of bioactive dietary components for

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

epigenetic effects upon changes in NAD+ availability and SIRT

6. Conclusion and future perspectives

different chromatin modiers, to reverse disease prone epigenetic

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

[189] Manachand C, Donovan JL. Pharmacokinetics and metabolism of dietary

W. Vanden Berghe / Pharmacological Research 65 (2012) 565576

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