Epigenetic targets of bioactive dietary components for cancer prevention and therapy
© Springer-Verlag 2010
Received: 4 August 2010
Accepted: 3 September 2010
Published: 18 September 2010
The emergent interest in cancer epigenetics stems from the fact that epigenetic modifications are implicated in virtually every step of tumorigenesis. More interestingly, epigenetic changes are reversible heritable changes that are not due to the alteration in DNA sequence but have potential to alter gene expression. Dietary agents consist of many bioactive ingredients which actively regulate various molecular targets involved in tumorigenesis. We present evidence that numerous bioactive dietary components can interfere with various epigenetic targets in cancer prevention and therapy. These agents include curcumin (turmeric), genistein (soybean), tea polyphenols (green tea), resveratrol (grapes), and sulforaphane (cruciferous vegetables). These bioactive components alter the DNA methylation and histone modifications required for gene activation or silencing in cancer prevention and therapy. Bioactive components mediate epigenetic modifications associated with the induction of tumor suppressor genes such as p21 WAF1/CIP1 and inhibition of tumor promoting genes such as the human telomerase reverse transcriptase during tumorigenesis processes. Here, we present considerable evidence that bioactive components and their epigenetic targets are associated with cancer prevention and therapy which should facilitate novel drug discovery and development. In addition, remarkable advances in our understanding of basic epigenetic mechanisms as well as the rapid progress that is being made in developing powerful new technologies, such as those for sensitive and quantitative detection of epigenetic and epigenomic changes in cancer biology, hold great promise for novel epigenetic approaches to cancer prevention and therapy.
KeywordsBioactive component Dietary polyphenol Cancer Epigenetic DNA methylation Histone modifications
Natural dietary agents including fruits, vegetables, and spices have been showing great potential in preventing and treating a wide variety of diseases including cancers. Dietary agents consist of many bioactive compounds that are ubiquitous in plants, many of which have been used as ancient traditional medicines. Dietary agents are not only an excellent source of fiber, vitamins, and minerals, but also contain bioactive components such as polyphenols, alkaloids, and phenolics that may serve more than a basic nutrition function. The bioactive components of dietary phytochemicals most often shown to be effective against cancer are tea polyphenols, genistein, curcumin, resveratrol, sulforaphane, isothiocyanates, silymarin, diallyl sulfide, lycopene, rosmarinic acid, apigenin, and gingerol. These bioactive components have shown great potential in preventing cancer through modifying genetic and epigenetic targets. In this analysis, we will focus on epigenetic targets of these bioactive dietary supplements associated with cancer prevention and therapy.
Epigenetics and cancer
“Geneticists study the gene; however, for epigeneticists, there is no obvious ‘epigene’” (Bird 2007). Nevertheless, epigenetics is typically defined as the study of reversible heritable changes in gene expression that are not due to alterations in DNA sequence. The term ‘epigenetic’ was coined by the developmental biologist, Conrad Hal Waddington, in 1942. Robin Holliday defined epigenetics as the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms (Holliday 1990). One of the best examples of epigenetic changes in eukaryotic biology is the different developmental stages from the single fertilized egg, the zygote, to a fully grown organism. Modern biology uses epigenetic changes as molecular tools for finding and treating various diseases including cancer. Cancer is a multi-step process derived from combinational crosstalk between genetic alterations and epigenetic influences through various environmental factors (Ducasse and Brown 2006; Esteller 2008; Ellis et al. 2009). Moreover, it has been well documented that environmental exposure to nutritional, dietary, physical, and chemical factors could alter gene expression and modify individual genetic susceptibility through changes in the epigenome (Issa 2008; Suter and Aagaard-Tillery 2009; Herceg 2007). Several distinct but intertwined mechanisms are known to be part of the epigenome which includes DNA methylation, histone acetylation, poly-ADP-ribosylation and ATP-dependent chromatin remodeling.
Epigenetic mechanisms controlling gene transcription are often involved in cell proliferation, differentiation, and survival and are casually linked with malignant development. Alterations in epigenetic processes including chromatin modifications such as DNA methylation and histone acetylation are common targets studied in cancer epigenomics (Herceg 2007; Esteller 2007). It has been shown that half of all tumor suppressor genes are inactivated in cancers more often by epigenetic, than by genetic, mechanisms (Issa 2008). Growing evidence suggests that bioactive dietary components impact epigenetic processes often involved with reactivation of tumor suppressor genes, activation of cell survival proteins, and induction of cellular apoptosis in many types of cancer (Landis-Piwowar et al. 2008; Li et al. 2010; Paluszczak et al. 2010; Majid et al. 2008). In addition to transcriptional silencing of tumor suppressor genes and protein expression, noncoding microRNAs (miRNAs) can regulate expression of a myriad of cellular proteins by affecting mRNA stability and translation by epigenetic processes in cancer progression (Esteller 2007; Ducasse and Brown 2006). Interestingly, these miRNAs can control the expression of various epigenetic modifying enzymes such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), and histone deacetylases (HDACs) involved in carcinogenesis processes (Guil and Esteller 2009; Saito and Jones 2006). Recent evidence suggests that bioactive dietary components can also target various oncogenic or tumor suppressive miRNAs to alter the gene expression profile in cancer prevention (Parker et al. 2009; Sun et al. 2009; Li et al. 2009b). In fact, miRNA profiles are now being used to classify human cancers (Calin et al. 2004). Further, miRNAs can directly or indirectly regulate cancer progression either by acting as tumor suppressors or by altering epigenetic modifying enzymes, respectively. In particular, miRNA-221 and miRNA-222 target KIT, an oncogene, and therefore function as tumor suppressors in erythroblastic cells and other human solid tumors (Croce 2009). Furthermore, the miRNA-29 family can directly regulate the expression of DNMTs and increase expression of DNMT3a and DNMT3b thereby causing a global genomic hypermethylation and silencing of methylation-sensitive tumor suppressor genes such as FHIT and WWOX (Fabbri et al. 2007).
In many disease processes such as cancer, gene promoter CpG islands acquire abnormal hypermethylation by altering DNMT expression and activity, which results in heritable transcriptional gene silencing. DNA methylation may impact the transcription of genes in two major ways. First, the methylation of DNA prevents binding of sequence specific transcriptional factors (e.g., AP-2, E2F, c-Myc) that require the presence of unmethylated CpG within the binding sites (Tate and Bird 1993). Second and likely more important is that methylated DNA may be bound by proteins known as methyl-CpG-binding domain (MBD) proteins. MBD proteins then recruit additional proteins, such as histone deacetylases and other chromatin-remodeling proteins that can modify acetylation and methylation status of histones to the locus thereby inhibiting transcriptional access to the chromatin. This subsequently leads to the formation of compact, inactive chromatin (Wade 2001; Ballestar and Wolffe 2001). The clinical aspects of DNA methylation are very important especially since DNA methylation is a reversible process and thereby leads to silencing or activation of particular genes for disease progression including cancer (Laird 2005).
In higher eukaryotes, DNA methylation is an enzymatic process that is primarily mediated by three enzymes; DNMT1, DNMT3a, and DNMT3b (Bestor 2000). DNMT1 is a ubiquitous enzyme considered the major methyltransferase for maintenance methylation, and the other two DNMTs serve as de novo methyltransferases. In human cells, DNMTs have some overlap in de novo and maintenance function. DNMTs have been showed to be an extensive molecular drug target for many available FDA-approved epigenetic drugs such as 5-azacytidine, commercially available as Vidaza, and 5-aza-2′-deoxycytidine, commercially available as Dacogen (Grønbaek et al. 2007; Kaminskas et al. 2005). In addition, the DNMT1 antisense oligonucleotide referred to as MG98 is currently under phase I clinical trials for patients with advanced solid tumors (Plummer et al. 2009). However, many of the most commonly used drugs produce meaningful results in less than half of the patients, and the use of higher doses often results in adverse side effects (Grønbaek et al. 2007). Another derivative of 5-azacytidine, zebularine, appears to be more stable than 5-azacytidine or 5-aza-2′-deoxycytidine, but has very narrow specificity towards cancer cells (Hellebrekers et al. 2007). Therefore, many cancer patients are exposed to highly toxic drugs and suffer from adverse side effects while receiving few therapeutic benefits (Eisenberg et al. 1998). Hence non-toxic and more effective dietary bioactive components have received wide attention in the use against various cancers for prevention and therapy. Extensive results have shown that bioactive dietary components have great potential in altering DNA methylation by modifying DNMTs levels in cancer prevention and therapy (Li and Tollefsbol 2010).
Epigenetic regulation has attracted considerable interest as a molecular target for cancer prevention and therapy as well as a target of bioactive food components. Many bioactive dietary components have shown promising results in direct or indirect inhibition of DNMT activity in cancer prevention and therapy. For example, (−)-epigallocatechin-3-gallate (EGCG), a major component of green tea, is known to complex with the DNMTs which reduces methylating activity in cancer cells leading to cancer prevention or therapy through epigenetic mechanisms (Fang et al. 2003; Mittal et al. 2003; Tsao et al. 2009). Furthermore, daily oral intake of EGCG in the form of Polyphenon E, a green tea extract, was well tolerated by chronic lymphocytic leukemia patients in phase I clinical trials (Shanafelt et al. 2009).
DNA methylation often suppresses gene expression, with some exceptions like the human telomerase reverse transcriptase (hTERT) gene (Berletch et al. 2008; Li et al. 2009a). Nevertheless, gene repression or activation is not determined by histone acetylation or methylation in general, but rather is determined by which residue is being modified, for example, trimethylation of lysine 4 on histone H3 (H3K4me3) is enriched for transcriptional gene activation, whereas trimethylation of lysine 9 on histone H3 (H3K9me3) and trimethylation of lysine 27 on histone H3 (H3K27me3) is present at gene promoters for transcriptional repression (Hebbes et al. 1988; Choudhuri et al. 2010). Further, enrichment of acetylation at lysine residues at gene promoter regions is associated with gene activation (Hebbes et al. 1988). Histone acetylation enhances chromatin accessibility by neutralizing the DNA–histone interactions which results in a relaxed, open chromatin conformation that allows the transcriptional activators to gain access to their cognate recognition elements and initiate/enhance transcription (Fig. 2) (Görisch et al. 2005; Lafon-Hughes et al. 2008).
Histone modifications are catalyzed by many enzymes such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs). HATs and HDACs add and remove acetyl group to the lysine residues present in histones, respectively, whereas HMTs and HDMs add and remove methyl groups to the different lysine or arginine resides in histones, respectively (Choudhuri et al. 2010). Further, arginine methylation is presumably transcription activating, whereas lysine methylation can cause either transcriptional activation or repression, depending on which lysine residue is being methylated (Choudhuri et al. 2010). Histone hypoacetylation at a promoter region, induced by either lack of HAT function or increased HDAC activity, results in silencing of the tumor suppressor gene, p21 WAF1/CIP1 , in tumorigenesis (Majid et al. 2008; Kikuno et al. 2008). By contrast, histone hyperacetylation at certain promoters through either increased HAT activity or decreased HDAC activity, results in an activation of normally repressed genes (Acharya et al. 2005; Kim et al. 2003). Collectively, the aberrant enrichment of HAT and HDAC activities may trigger carcinogenesis processes (Mottet and Castronovo et al. 2008).
It has been widely recognized that HDACs are promising targets in the field of oncology and epigenetic therapy (Davis and Ross 2007; Marsoni et al. 2008). An impressive body of preclinical research points to the ability of HDAC inhibitors (HDACIs) to modulate a wide variety of cellular functions, including cellular differentiation, cell cycle progression, apoptosis, cytoskeleton modifications, and angiogenesis (Marsoni et al. 2008). Thus, the use of HDACIs is considered a potent strategy in cancer prevention and epigenetic therapy. An extensive list of HDACIs has been purified from natural sources or synthetically developed, and many of these HDACIs have advanced to clinical applications (Bolden et al. 2006). HDACIs such as trapoxin, trichostatin A, and suberoylanilide hydroxamic acids (SAHAs) are among the most studied and have more global HDAC inhibition activity. Vorinostat or SAHA (brand name Zolinza) is a commercially available FDA-approved HDACI for treatment of cutaneous T-cell lymphoma (Ellis et al. 2009). Many other HDACIs are in different phases of clinical trials such as panobinostat (LBH589), belinostat (PXD101), TF2357, PCI-24781, phenylbutyrate, romidepsin (depsipeptide), MS-275, MS-275 and, MGCD0103 (Ellis et al. 2009).
Besides synthetic HDACIs, many bioactive dietary components have shown promising results in direct or indirect inhibition of HDAC activity as well as other histone modification activities in cancer prevention and therapy (Nian et al. 2009; Myzak et al. 2006c). For example, sulforaphane (SFN), a major component present in cruciferous vegetables, inhibits HDAC activity, at least partially, by direct interaction with the HDAC active sites (Myzak et al. 2004). In an another study, SFN has been shown to result in HDAC inhibition in human volunteers consuming SFN-rich broccoli sprouts, and the SFN-induced HDAC inhibition increased histone acetylation in peripheral blood cells of the human subjects without adverse effects (Myzak et al. 2006a, 2007).
Bioactive dietary components and epigenetic targets
The tea plant Camellia sinesis is cultivated in more than 30 countries. Tea is consumed worldwide and next to water is the most consumed beverage in the world, with an average per capita consumption of ~120 mL/day (Mukhtar and Ahmad 2000). Epidemiologic observations and laboratory studies have indicated that polyphenolic compounds present in tea may reduce the risk of a variety of diseases, including coronary heart disease and cancer. The most abundant chemical compound in green tea beverages is catechins, which include (−)-epicatechin (EC), (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC), and (−)-epigallocatechin-3-gallate (EGCG) (Graham 1992). Of these, EGCG accounts for more than 50% of the total polyphenol and effective content in green tea (Lin and Liang 2000). EGCG has been identified as a major and most effective constituent of green tea. Therefore, the large majority of the in vitro and in vivo studies of the effects of green tea have been conducted using EGCG.
EGCG has been shown to induce apoptosis and cell cycle arrest in many cancer cells without affecting normal cells (Ahmad et al. 1997; Gu et al. 2009). Therefore, it is likely that EGCG imparts its anti-cancer effects through many different mechanisms (Balasubramanian et al. 2010; Fassina et al. 2004; Huh et al. 2004). One mechanism includes the inhibition of DNMT1 leading to demethylation and reactivation of methylation-silenced genes. Treatment of human esophageal KYSE 510 and 150 cells with EGCG has been shown to lower DNMT1 activity and to lead to hypomethylation and re-expression of genes including p16 INK4a , retinoic acid receptor β (RARβ), O6-methylguanine methyltransferase (MGMT), and human mutL homologue 1 (hMLH1) (Fang et al. 2003). In another study with oral carcinoma cells, EGCG partially reversed the hypermethylation status of RECK, a tumor suppressor gene, and significantly enhanced the expression level of RECK mRNA. EGCG-induced epigenetic reactivation of RECK is important since it negatively regulates matrix metalloproteinases (MMPs) and inhibits tumor invasion, angiogenesis, and metastasis (Kato et al. 2008). Pandey et al. (2010) demonstrated that exposure of human prostate cancer LNCaP cells to 1–10 μg/ml of green tea polyphenol for 1–7 days caused a concentration- and time-dependent re-expression of a known precursor to the genesis of prostate cancer, gluthathione-S-transferase pi (GSTP1), which correlated with DNMT1 inhibition.
Recently, it has been observed that tea polyphenols [catechin, epicatechin, and EGCG and bioflavonoids (quercetin, fisetin, and myricetin)] inhibited SssI DNMT- and DNMT1-mediated DNA methylation in a concentration-dependent manner. The IC50 values for catechin, epicatechin, and various flavonoids ranged from 1.0 to 8.4 μM, but EGCG was a more potent inhibitor, with IC50 values ranging from 0.21 to 0.47 μM (Lee et al. 2005). A molecular modeling study demonstrated that EGCG exerts its inhibitory effect on DNMT1 function by blocking entry of the key nucleotide cytosine into its active site by hydrogen bonds and, thus, prevents DNA methylation (Fang et al. 2003). Furthermore, the presence of Mg2+ can enhance the binding force of EGCG and the DNMTs by stabilizing their binding interactions nearly ten times more than without Mg2+ presence (Lee et al. 2005). Here, we discuss most of the epigenetic targets altered by EGCG, but other catechins such as EC, ECG, and EGC have also been found to share similar properties although they are less efficient than EGCG (Fang et al. 2003; Lee et al. 2005).
Besides direct inhibition of DNMT by EGCG, it was also reported that consumption of polyphenols could lead to a decrease in available S-adenosyl-L-methionine (SAM) and an increase in S-adenosyl-L-homocysteine (SAH) and homocysteine levels, thereby providing evidence of an indirect inhibition of DNA methylation by EGCG (Lee and Zhu 2006). This conjecture is supported by animal studies demonstrating that EGCG consumption through drinking water can moderately decrease the level of SAM (without increasing the level of SAH) in the intestine (Fang et al. 2007).
EGCG not only reactivates tumor suppressor genes by inhibiting DNA methylation but also inhibits tumor promoter genes such as hTERT, a catalytic subunit of telomerase (Berletch et al. 2008). In most cases, hypermethylation of the regulatory region of a gene can inhibit its expression. For example, the p16 INK4a promoter becomes methylated during tumorigenesis leading to inhibition of its expression (Lee et al. 2003). Interestingly, hTERT regulation by DNA methylation goes against the paradigm, and hypermethylation of its promoter leads to increased expression in cancer cells (Guilleret and Benhattar 2004; Quante et al. 2005). One possible reason for this paradox was shown in breast cancer cells were EGCG-induced progressive demethylation of the hTERT promoter which allowed the E2F-1 repressor of hTERT to bind to its promoter and inhibit its expression (Berletch et al. 2008). Another classical example for EGCG-induced promoter demethylation inhibiting an oncogene is Wingless-type (Wnt) which occurs through epigenetic reactivation of Wnt inhibitory factor-1 (WIF-1) in lung cancer cells (Gao et al. 2009). The Wnt family consists of a group of signaling molecules that is extensively involved in developmental processes and oncogenesis. WIF-1 is a Wnt antagonist that inhibits Wnt signaling by direct binding to Wnt molecules (Gao et al. 2009).
EGCG is unstable under physiological conditions, and methylation of EGCG by COMT is a modification that reduces the biological activity of EGCG (Landis-Piwowar et al. 2010). Recently, Moiseeva et al. (2007) showed that low-dose long-term exposure of bioactive components such as EGCG and genistein results in epigenetic alterations of gene expression, reduced growth, and increased cellular apoptosis in breast cancer cells. Furthermore, there are several synthetic analogs of EGCG that have been shown to have strong anti-cancer activity with more efficacy and stability than EGCG under physiological conditions (Kanwar et al. 2010; Huo et al. 2010; Landis-Piwowar et al. 2007). However, their epigenetic roles in cancer prevention and therapy have not yet been reported.
Although various studies have shown that green tea polyphenol or EGCG can effectively inhibit carcinogenesis in various animal organs (Tran et al. 2010; Liang et al. 2010; Sagara et al. 2010; Zhang et al. 2010), their epigenetic effects have been largely undetermined. Morey Kinney et al. (2009) demonstrated that administration of 0.3% green tea polyphenols (GTPs) to wild-type (WT) and transgenic adenocarcinoma of mouse prostate (TRAMP) mice showed no alteration in 5-methyl-deoxycytidine (5mdC) levels in prostate, gut, and liver from WT mice at both 12 and 24 weeks of age, with the single exception of a decrease of 5mdC in the liver at 12 weeks. Quite surprisingly, GTPs treatment did not inhibit tumor progression in TRAMP mice, although known pharmacodynamic markers of GTPs such as Ssat and Clustrin mRNA levels were altered in both WT and TRAMP prostates. However, Mittal et al. (2003) demonstrated that topical application of EGCG inhibits ultraviolet-B (UVB)-induced photocarcinogenesis by UVB-induced global DNA hypomethylation in SKH-1 hairless mouse model system. Both immunohistochemical analyses of 5mdC and DNMTs activities were restored significantly by topical application of EGCG in a chronic UVB-induced SKH-1 hairless mouse model system (Mittal et al. 2003). Studies have strongly correlated dietary habits and physical activity in relation to epigenetic reactivation of several genes, including tumor suppressor genes (Yuasa et al. 2009; Yun et al. 2010a). Yuasa et al. (2005) demonstrated in primary gastric carcinoma patients that past life style and dietary habits including consumption of cruciferous vegetables and GTPs alter the methylation status of several genes such as CDX2 and BMP-2, which are important for preventing gastric carcinogenesis. Recently, Volate et al. (2009) showed that administration 0.6% (w/v) GTPs in drinking water to azoxymethane-treated Apc Min/+ mice showed a significant decrease in CpG methylation in the retinoic X receptor alpha gene promoter leading to inhibition of intestinal tumorigenesis.
The disruptions of histone acetylation/deacetylation balances by bioactive components through regulation of HAT and HDAC activities have received considerable attention in cancer prevention and therapy. In addition to DNA methylation inhibitory activity, EGCG also regulates gene expression through changes in histone modifications. Recently, Choi et al. (2009) discovered that EGCG has strong HAT inhibitory activity among all other catechins screened in various cell extracts from B lymphocytes, and the order of HAT inhibition by catechins is EGCG > EGC > EC. In the same study, it was discovered that EGCG abrogates p300-induced p65 acetylation in vitro and in vivo, increases the level of cytosolic IκBα, and suppresses tumor necrosis factor α-induced NF-κB activation. EGCG-induced p65 deacetylation events led to a cytoplasmic accumulation of IκBα and subsequent cytosolic sequestration of NF-κB resulting in the downstream inhibition of inflammatory genes such as IL-6, COX-2, and NOS2 (Choi et al. 2009). Further, they found that EGCG does not make any significant changes in HDACs, HMTs, and SIRT1 in their assay system. However, studies with human prostate cancer LNCaP cells showed that exposure to 1–10 μg/ml of GTPs for 1–7 days caused time-dependent inhibition of HDAC1-3 expression and increased the levels of acetylated histone H3 (LysH9/18) and H4 levels (Pandey et al. 2010). GTPs-induced histone acetylation and promoter demethylation reactivated the GSTP1 gene, which is an important hallmark in prostate tumorigenesis.
Studies have also been initiated using combinations of GTPs with known HDAC inhibitors to enhance DNMT inhibition and HDAC inhibition activities, respectively, for effective chemoprevention (Nair et al. 2008). Recently, Nihal et al. (2010) showed that combined use of GTPs with vorinostat, known as SAHA, a HDAC inhibitor, imparts significant anti-proliferative effects against human melanoma cells. The demethylating activity of EGCG may synergize with the HDAC inhibitory action of vorinostat to help de-repress silenced tumor suppressor genes regulating key functions such as proliferation and cell survival. In keeping with this view, they showed a greater anti-melanoma effect with the combination of EGCG and vorinostat than either agent alone (Nihal et al. 2010). There is very limited evidence regarding in vivo histone modification effects of GTPs. A study with dimethylaminoazobenzene-induced hepatocarcinogenesis in male Sprague–Dawley rats showed that administration of 0.05% (w/w) Polyphenon E (from black tea polyphenol) induced a significant decrease in HDAC1 expression compared to animals fed a control diet (Murugan et al. 2009).
Sulforaphane (SFN), an isothiocyanate naturally rich in widely consumed cruciferous vegetables such as broccoli, broccoli sprouts, cabbage, and kale, has been shown to reduce the risk of developing many common cancers (Higdon et al. 2007; Pledgie-Tracy et al. 2007; Keum et al. 2009; Cheung and Kong 2010). SFN mediates chemoprevention through several mechanisms including cell cycle arrest and induction of apoptosis and phase 2 detoxification enzymes (Bryant et al. 2010; Chu et al. 2009; Dinkova-Kostova et al. 2007; Bacon et al. 2003). However, there has been growing interest in epigenetic regulation by SFN in chemoprevention due to its histone deacetylase (HDAC) inhibition activity (Myzak et al. 2007; Dashwood and Ho 2007; Ho et al. 2009). The HDAC inhibition activity of SFN has been shown to lead to an increase in the global and local histone acetylation status of a number of genes (Bhamre et al. 2009; Telang et al. 2009; Dashwood and Ho 2008). SFN-mediated epigenetic alterations are believed to be strongly involved in the process of cancer chemoprevention by altering the expression of various genes, including tumor suppressor genes in various cancers (Herman-Antosiewicz et al. 2007).
SFN was found to inhibit DNMTs in MCF-7 and MDA-MB-231 breast cancer as well as CaCo-2 colon cancer cells (Meeran et al. 2010; Traka et al. 2005). Meeran et al. (2010) demonstrated that SFN treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT), the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells and that it had negligible effects on normal control cells. Further, DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells. More interestingly, down-regulation of DNMTs induced site-specific CpG demethylation occurring primarily in the first exon of the hTERT gene thereby facilitating CTCF binding associated with hTERT repression followed by cellular apoptosis in breast cancer cells (Meeran et al. 2010).
SFN has also been found to have HDAC inhibitory activity in many other cancer in vitro and in vivo cancer models. SFN dose-dependently increased the activity of a beta-catenin-responsive reporter (TOPflash) and diminished HDAC activity in human embryonic kidney 293 cells (Myzak et al. 2004). In HCT116 human colorectal cancer cells, SFN inhibited HDAC activity thereby increasing histone acetylation at the p21WAF1/CIP1 promoter to enhance its expression (Myzak et al. 2004). Human prostate cancer BPH-1, LNCaP, and PC-3 cells also showed significant inhibition of HDAC activity by SFN treatment. Further, SFN-induced histone acetylation increased the expression of the p21WAF1/CIP1 protein, thereby inhibiting cell cycle arrest and inducing cellular apoptosis in these prostate cancer cell lines (Myzak et al. 2006b; Ho et al. 2009).
SFN also has HDAC inhibitory effects in vivo as shown in animal and human models. Myzak et al. (2006a) demonstrated that mice treated with a single oral dose of 10 μM SFN had significant HDAC inhibitory activity in colonic mucosa with increased acetylated histones H3 and H4. Further, the authors demonstrated that increased acetylation enhanced the expression of p21 WAF1/CIP1 and bax gene expressions, thereby suppressing tumorigenesis in Apc/+ mice (Myzak et al. 2006a). Another study demonstrated that administration of 7.5 μM SFN per animal for 21 days significantly reduced prostate cancer PC-3 tumor xenografts by inhibiting HDAC activity in vivo (Myzak et al. 2007). Importantly, in human subjects, a single dose of 68 g of broccoli sprouts inhibited HDAC activity significantly in peripheral blood mononuclear cells at 3 and 6 h following consumption (Myzak et al. 2007). Following oral dosing, sulforaphane metabolites were readily measurable in human breast tissue enriched for epithelial cells (Cornblatt et al. 2007). Collectively, SFN has been found to be a potent HDAC inhibitor both in vitro and in vivo models.
Genistein is an isoflavone belonging to the flavonoids group of compounds and is found in a number of plants including fava beans, soybeans, lupin, kudzu, and psoralea. Genistein and other isoflavones have been found to have anti-cancer and anti-angiogenic properties in various cancers. Several studies have found moderate doses of genistein to have inhibitory effects on cancers of the prostate, cervix, brain, breast, and colon (Barnes 1995). It is becoming increasingly clear that genistein exerts multiple effects on cancer cell growth. Several mechanisms for the anti-proliferative and anti-cancer properties of genistein have been found, including prevention of DNA mutation, reduction in cancer cell proliferation, inhibition of angiogenesis, and induction of cellular apoptosis (Singh et al. 2006; Gu et al. 2005; Su et al. 2005; Sasamura et al. 2004). One potential mechanism that has recently received considerable attention is that genistein is involved in regulation of gene transcription or silencing activity by modulating epigenetic events such as DNA methylation and/or chromatin modifications (Li and Tollefsbol 2010; Li et al. 2009a; Kikuno et al. 2008).
Several reports have found that genistein has DNA methyltransferase inhibitory activity as well as histone modification properties in cancer cells. In prostate cancer cells, genistein induced the expression of the tumor suppressor genes p21 WAF1/CIP1 and p16 INK4a by altering promoter methylation and histone modification (Majid et al. 2008; Kikuno et al. 2008). Further, it was found that genistein increased acetylated histones 3 and 4 and H3-lysine4 at the p21 WAF1/CIP1 and p16 INK4a transcription start sites, mediated by induction of HATs. Genistein-mediated promoter hypomethylation and hyperacetylation reactivate expression of tumor suppressor genes in human prostate cancer cells and are followed by cell cycle arrest and cellular apoptosis induced by cyclin and caspase pathways, respectively (Majid et al. 2008; Kikuno et al. 2008). This dietary bioactive compound also reactivates BTG3, a tumor suppressor gene, in A498, ACHN, and HEK-293 renal carcinoma cell lines (Majid et al. 2009). Genistein activates the epigenetic re-expression of BTG3 by altering promoter DNA methylation through inhibition of DNMTs and methyl-CpG-binding domain 2 in these cells, whereas, genistein also increases histone acetylation by enhancing HAT activity, followed by enrichment of acetylated histones 3 and 4, dimethyl-H3K4, and trimethyl-H3K4 near the transcription start site at the BTG3 gene promoter (Majid et al. 2009). This is consistent with other reports that genistein upregulated mRNA expression of the BRAC1, p16 INK4a , RARb, MGMT, and p21 WAF1/CIP1 genes (Majid et al. 2008; Fang et al. 2005). Studies have also shown that genistein in combination with other DNA methyltransferases or HDAC inhibitors enhanced the reactivation of methylation-silenced genes (Raynal et al. 2008; Li et al. 2009a; Fang et al. 2005).
Genistein not only reactivates tumor suppressor genes through epigenetic modifications but also inhibits the expression of tumor promoter genes such as hTERT. Genistein inhibits DNMT1, DNMT3a, and DNMT3b and enriches inactivating histone trimethyl-H3K9 followed by transcriptional repression of hTERT expression in human breast cancer cells (Li et al. 2009a). In another study with MDA-MB-468 human breast cancer cells, low concentrations of genistein partially demethylated the GSTP1 tumor suppressor gene promoter and reactivated its expression (King-Batoon et al. 2008).
In addition to in vitro epigenetic modulation, genistein-treated neonatal CD-1 mice showed anomalously hypomethylated nucleosomal binding protein-1 promoter than hypermethylated control (non-genistein) treated mice (Tang et al. 2008). In contrast to genistein-induced DNA hypomethylation mediated through DNMT inhibition, studies also have shown that genistein induced hypermethylation in some animal models (Day et al. 2002; Guerrero-Bosagna et al. 2008). In accordance with animal studies, genistein also increased hypermethylation in human studies randomized with selective cancer-related genes. Thirty-four healthy premenopausal women were randomized to take 40 or 140 mg isoflavones daily through one menstrual cycle, and the methylation status of p16 INK4a , RASSF1A, RARβ2, ER and CCND2 were assessed in intraductal specimens. The results showed that RARβ2 and CCND2 were hypermethylated after genistein administration, and these results correlated well with serum genistein levels (Qin et al. 2009).
Curcumin, a yellow pigment present in the spice turmeric (Curcuma longa), has been linked with multiple beneficial activities including anti-inflammatory, anti-angiogenic and wound-healing, antioxidant, and anti-cancer properties. Curcumin has been shown in various animal models and human studies to be extremely safe even at very high doses; however, their solubility and bioavailability is an obstacle for therapeutic drug development (Aggarwal et al. 2003; Shishodia et al. 2007). Curcumin-mediated chemoprevention is mainly facilitated through cell cycle arrest and induction of cellular apoptosis in various cancer cells. Curcumin-induced apoptosis is involved with the intrinsic and extrinsic apoptosis pathways, the NF-κB-mediated pathway as well as the PI3K/Akt signaling pathway (Reuter et al. 2008). Recent evidence has shown that curcumin also inhibits DNMT activities and histone modification such as HDAC inhibition in tumorigenesis (Fu and Kurzrock 2010).
Molecular docking of the interaction between curcumin and DNMT1 suggested that curcumin covalently blocks the catalytic thiolate of C1226 of DNMT1 to exert its inhibitory effect (Liu et al. 2005). This inhibition seems to be comparatively lower than other bioactive dietary components such as EGCG and genistein (Fang et al. 2007; Liu et al. 2005). Further, curcumin treatment with extracted genomic DNA from a leukemia cell line induced global hypomethylation (Liu et al. 2005). These results provide strong evidence that curcumin is a potent DNA hypomethylating agent, which is important for its broad-spectrum inhibitory activity in inflammation, cancer, and many other diseases.
Curcumin also has strong inhibitory activity against HDACs and HATs in several in vitro cancer models. Curcumin showed strong proliferation inhibition potency on Burkitt’s lymphoma Raji cells in vitro, with the IC50 value for 24 h at 25 μM. Significant decreases in the amounts of p300, HDAC1, HDAC3, and HDAC8 were detected after treatment with curcumin followed by prevention of IkappaB alpha degradation and inhibition of nuclear translocation of the NF-κB/p65 subunit (Chen et al. 2007; Liu et al. 2005). Meja et al. (2008) demonstrated that even very low concentrations of curcumin (30 and 200 nM) restored corticosteroid function in human monocytes exposed to oxidants. This occurred by maintaining HDAC2 activity via preventing oxidant-induced degradation of HDAC2 through down-regulating gene expression associated with protein degradation.
Curcumin has been identified as a strong inhibitor for HATs in both in vitro and in vivo cancer models. One of the early epigenetic studies showed that curcumin is a specific inhibitor of p300/CREB-binding protein (CBP) HAT activity but not of p300/CBP-associated factor, in vitro and in vivo. Curcumin-mediated p300/CBP inhibition was associated with repression of histones H3 and H4 and non-histone protein such as p53 and HIV-TAT proteins (Balasubramanyam et al. 2004). Another structural analysis study done by Marcu et al. (2006) revealed that alpha, beta unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites, which is required for its HAT inhibitory activity. Further, they demonstrate that curcumin selectively promotes proteasome-dependent degradation of p300 and closely related CBP protein without affecting the HATs such as PCAF or GCN5 in prostate PC3-M and peripheral blood lymphocytes. Interestingly, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the HDAC inhibitor MS-275 (Marcu et al. 2006).
Kang et al. (2006) showed a strong inhibition of curcumin-mediated HAT inhibitory activity associated with a decrease in histone H3 and H4 acetylation in brain cancer cells. Further, curcumin-induced histone modifications associated with caspases-mediated cellular apoptosis in brain cancer cells and enhanced neurogenesis, synaptogenesis, and migration of neural progenitor cells in brain-derived adult neural stem cells in vitro (Kang et al. 2006). Another study demonstrated that curcumin restored ultraviolet radiation-induced hyperacetylation in the promoter region of ATF3, COX2, and MKP1, which are inflammatory-related genes in human keratinocytes (Pollack et al. 2009). Further, studies have also shown that curcumin-mediated promoter hypoacetylation of certain genes was strongly correlated with gene silencing (Cui et al. 2007; Pollack et al. 2009). A very recent study showed that curcumin inhibits high glucose-induced proinflammatory cytokines by epigenetic modification in human monocytic (THP-1) cells. It was demonstrated that curcumin treatment significantly reduced HAT activity, p300 and acetylated CBP/p300 gene expression, and induced HDAC2 expression in THP-1 cells, thereby inhibiting high glucose-induced proinflammatory cytokines, which is an important molecular target in reducing diabetic complications (Yun et al. 2010b).
In animal models, curcumin is found to be protective against cardiac failure, inflammation, and fibrosis through down-regulation of NFκB, GATA4, and TGFβ signaling as well as inhibition of HAT activity in rats (Morimoto et al. 2008; Li et al. 2008). Curcumin was also found to be very effective against streptozotocin-induced diabetes in male Sprague–Dawley rats through the inhibition of H3 hyperacetylation, NFκB binding, and p300 and H3S10 phosphorylation (Chiu et al. 2009; Tikoo et al. 2008).
Resveratrol is a dietary polyphenol derived from grapes, berries, peanuts, and other plant sources. Resveratrol was found to have strong anti-cancer properties by modulating signal transduction pathways that control cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis (Bishayee 2009). The anti-cancer property of resveratrol has been supported by its ability to inhibit proliferation of a wide variety of human tumor cells such as in skin, breast, prostate, lung, and colon (Mao et al. 2010; Vanamala et al. 2010; Liu et al. 2010; Kraft et al. 2009). These in vitro results have led to numerous preclinical animal studies to evaluate the potential of this drug for cancer chemoprevention and chemotherapy. Multiple biochemical and molecular actions seem to contribute to resveratrol effects against precancerous or cancer cells (Athar et al. 2009).
Resveratrol has been shown to have weaker DNMT inhibitory activity than other dietary bioactive components such as EGCG. Resveratrol prevents epigenetic silencing of BRCA-1 induced by aromatic hydrocarbon receptor (AHR) in MCF-7 human breast cancer cells (Papoutsis et al. 2010). It was demonstrated that AHR-mediated enrichment of mono-methylated-H3K9, DNMT1, and methyl-binding domain protein-2 at BRCA-1 promoter was restored, at least partially by resveratrol treatment, which was associated with BRAC-1 reactivation in MCF-7 cells (Papoutsis et al. 2010). In contrast, resveratrol did not significantly induce retinoic acid receptor beta 2 (RARβ 2) expressions by inhibiting RARβ2 promoter methylation in MCF-7 cells compared to other adenosine analogs (Stefanska et al. 2010).
Studies have shown that resveratrol is associated with activation of the type III HDAC inhibitors, sirtuin 1 (SIRT1), and p300, in multiple in vitro and in vivo models (Kaeberlein et al. 2005). The activated SIRT1 negatively regulates Survivin expression through its deacetylase activity. Wang et al. (2008) found that human BRCA1-associated breast cancers have lower levels of SIRT1 expression. However, bioactive dietary components associated with SIRT1 activation mediated an increased expression of human BRAC1 by altering H3 acetylation, which is an important strategy for targeted therapy for BRCA1-associated breast cancer (Wang et al. 2008). In addition, SIRT1-associated BRAC1 signaling is important for inhibiting tumorigenesis by activating oncoproteins in human breast cancer cells (Wang et al. 2008). It was shown in APC/+ mice that SIRT1-encoded proteins are required for resveratrol-mediated chemoprevention (Boily et al. 2009). SIRT1 also plays important roles in aging processes, since SIRT1-null mice could not tolerate caloric restriction and did not extend their lifespan compared to control mice (Boily et al. 2008).
Other bioactive components
In addition to the aforementioned bioactive components, other common fruits and vegetables have also been reported to have epigenetic targets either through DNMT inhibition or histone modifications. These bioactive compounds include apigenin (parsley), baicalein (Indian trumpet), cyanidins (grapes), isothiocyanate (cruciferous vegetables), rosmarinic acid (rosemary), and silymarin (milk thistle). All of these bioactive components have been reported to have either direct or indirect epigenetic targets in cancer chemoprevention and therapy (Davis and Ross 2007; Fang et al. 2007; Paluszczak et al. 2010; King-Batoon et al. 2008; Li and Tollefsbol 2010).
Conclusion and future directions
The emerging field of nutritional genomics targets nutrient-related genetic and epigenetic changes for prevention and therapy of various diseases including cancer. From the studies described herein, it is clear that bioactive dietary components hold great potential not only in the prevention but also in the therapy of a wide variety of cancers by altering various epigenetic modifications. Cancer is a multi-step processes and uses many survival pathways to prevail over normal cells. Therefore, bioactive components which have numerous molecular targets and suppress multiple cellular pathways such as EGCG may have strong potential for cancer prevention and treatment. Although individual bioactive components have shown great potential in prevention and treatment of various cancers, the combined use of dietary components should be more efficient in targeting the many cellular processes involved in tumorigenesis. Additional clinical studies are required to analyze the safety profile of doses, route of administration, organ specificity, and bioavailability of these bioactive components in human subjects. Ancient medicinal uses and extant scientific evidence strongly endorse the use of these bioactive dietary components for drug discovery and development against cancer prevention and therapy.
This work was supported by grant R01 CA129415 from the National Cancer Institute, National Institutes of Health.
Conflict of interest
The authors declare that they have no conflict of interest.
- Acharya M, Sparreboom A, Venitz J, Figg W (2005) Rational development of histone deacetylase inhibitors as anticancer agents: a review. Mol Pharmacol 68:917–932PubMedGoogle Scholar
- Aggarwal B, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421PubMedGoogle Scholar
- Aggarwal B, Kumar A, Bharti A (2003) Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 23:363–398PubMedGoogle Scholar
- Ahmad N, Feyes D, Nieminen A, Agarwal R, Mukhtar H (1997) Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 89:1881–1886PubMedGoogle Scholar
- Athar M, Back J, Kopelovich L, Bickers D, Kim A (2009) Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys 486:95–102PubMedPubMed CentralGoogle Scholar
- Bacon JR, Williamson G, Garner RC, Lappin G, Langouet S, Bao Y (2003) Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes. Carcinogenesis 24:1903–1911PubMedGoogle Scholar
- Balasubramanian S, Adhikary G, Eckert RL (2010) The Bmi-1 polycomb protein antagonizes the (-)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival. Carcinogenesis 31:496–503PubMedPubMed CentralGoogle Scholar
- Balasubramanyam K, Varier R, Altaf M, Swaminathan V, Siddappa N, Ranga U, Kundu T (2004) Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 279:51163–51171PubMedGoogle Scholar
- Ballestar E, Wolffe A (2001) Methyl-CpG-binding proteins. Targeting specific gene repression. Eur J Biochem 268:1–6PubMedGoogle Scholar
- Barnes S (1995) Effect of genistein on in vitro and in vivo models of cancer. J Nutr 125:777S–783SPubMedGoogle Scholar
- Berletch JB, Liu C, Love WK, Andrews LG, Katiyar SK, Tollefsbol TO (2008) Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG. J Cell Biochem 103:509–519PubMedPubMed CentralGoogle Scholar
- Bestor T (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2402PubMedGoogle Scholar
- Bhamre S, Sahoo D, Tibshirani R, Dill D, Brooks J (2009) Temporal changes in gene expression induced by sulforaphane in human prostate cancer cells. Prostate 69:181–190PubMedPubMed CentralGoogle Scholar
- Bird A (2007) Perceptions of epigenetics. Nature 447:396–398PubMedGoogle Scholar
- Bishayee A (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res (Phila Pa) 2:409–418Google Scholar
- Boily G, Seifert EL, Bevilacqua L, He XH, Sabourin G, Estey C, Moffat C, Crawford S, Saliba S, Jardine K, Xuan J, Evans M, Harper ME, McBurney MW (2008) SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE 3:e1759PubMedPubMed CentralGoogle Scholar
- Boily G, He XH, Pearce B, Jardine K, McBurney MW (2009) SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 28:2882–2893PubMedGoogle Scholar
- Bolden J, Peart M, Johnstone R (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5:769–784PubMedGoogle Scholar
- Bryant CS, Kumar S, Chamala S, Shah J, Pal J, Haider M, Seward S, Qazi AM, Morris R, Semaan A, Shammas MA, Steffes C, Potti RB, Prasad M, Weaver DW, Batchu RB (2010) Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells. Mol Cancer 9:47PubMedPubMed CentralGoogle Scholar
- Calin G, Sevignani C, Dumitru C, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce C (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 101:2999–3004PubMedPubMed CentralGoogle Scholar
- Chen Y, Shu W, Chen W, Wu Q, Liu H, Cui G (2007) Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. Basic Clin Pharmacol Toxicol 101:427–433PubMedGoogle Scholar
- Cheung KL, Kong AN (2010) Molecular targets of dietary phenethyl isothiocyanate and sulforaphane for cancer chemoprevention. AAPS J 12:87–97PubMedPubMed CentralGoogle Scholar
- Chiu J, Khan Z, Farhangkhoee H, Chakrabarti S (2009) Curcumin prevents diabetes-associated abnormalities in the kidneys by inhibiting p300 and nuclear factor-kappaB. Nutrition 25:964–972PubMedGoogle Scholar
- Choi KC, Jung MG, Lee YH, Yoon JC, Kwon SH, Kang HB, Kim MJ, Cha JH, Kim YJ, Jun WJ, Lee JM, Yoon HG (2009) Epigallocatechin-3-gallate, a histone acetyltransferase inhibitor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. Cancer Res 69:583–592PubMedGoogle Scholar
- Choudhuri S, Cui Y, Klaassen C (2010) Molecular targets of epigenetic regulation and effectors of environmental influences. Toxicol Appl Pharmacol 245:378–393PubMedPubMed CentralGoogle Scholar
- Chu WF, Wu DM, Liu W, Wu LJ, Li DZ, Xu DY, Wang XF (2009) Sulforaphane induces G2-M arrest and apoptosis in high metastasis cell line of salivary gland adenoid cystic carcinoma. Oral Oncol 45:998–1004PubMedGoogle Scholar
- Cornblatt BS, Ye L, Dinkova-Kostova AT, Erb M, Fahey JW, Singh NK, Chen MS, Stierer T, Garrett-Mayer E, Argani P, Davidson NE, Talalay P, Kensler TW, Visvanathan K (2007) Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis 28:1485–1490PubMedGoogle Scholar
- Croce C (2009) Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10:704–714PubMedPubMed CentralGoogle Scholar
- Cui L, Miao J, Furuya T, Li X, Su XZ (2007) PfGCN5-mediated histone H3 acetylation plays a key role in gene expression in Plasmodium falciparum. Eukaryot Cell 6:1219–1227PubMedPubMed CentralGoogle Scholar
- Dalvai M, Bystricky K (2010) The role of histone modifications and variants in regulating gene expression in breast cancer. J Mammary Gland Biol Neoplasia 15:19–33PubMedGoogle Scholar
- Dashwood RH, Ho E (2007) Dietary histone deacetylase inhibitors: from cells to mice to man. Semin Cancer Biol 17:363–369PubMedPubMed CentralGoogle Scholar
- Dashwood R, Ho E (2008) Dietary agents as histone deacetylase inhibitors: sulforaphane and structurally related isothiocyanates. Nutr Rev 66(Suppl 1):S36–S38PubMedPubMed CentralGoogle Scholar
- Davis CD, Ross SA (2007) Dietary components impact histone modifications and cancer risk. Nutr Rev 65:88–94PubMedGoogle Scholar
- Day J, Bauer A, DesBordes C, Zhuang Y, Kim B, Newton L, Nehra V, Forsee K, MacDonald R, Besch-Williford C, Huang T, Lubahn D (2002) Genistein alters methylation patterns in mice. J Nutr 132:2419S–2423SPubMedGoogle Scholar
- Dinkova-Kostova AT, Fahey JW, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ, Kerns ML, Talalay P (2007) Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. Cancer Epidemiol Biomark Prev 16:847–851Google Scholar
- Druesne N, Pagniez A, Mayeur C, Thomas M, Cherbuy C, Duée P, Martel P, Chaumontet C (2004) Diallyl disulfide (DADS) increases histone acetylation and p21(waf1/cip1) expression in human colon tumor cell lines. Carcinogenesis 25:1227–1236PubMedGoogle Scholar
- Ducasse M, Brown M (2006) Epigenetic aberrations and cancer. Mol Cancer 5:60PubMedPubMed CentralGoogle Scholar
- Eisenberg D, Davis R, Ettner S, Appel S, Wilkey S, Van Rompay M, Kessler R (1998) Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 280:1569–1575PubMedGoogle Scholar
- Ellis L, Atadja P, Johnstone R (2009) Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther 8:1409–1420PubMedGoogle Scholar
- Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298PubMedGoogle Scholar
- Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159PubMedGoogle Scholar
- Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, Liu S, Alder H, Costinean S, Fernandez-Cymering C, Volinia S, Guler G, Morrison C, Chan K, Marcucci G, Calin G, Huebner K, Croce C (2007) MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA 104:15805–15810PubMedPubMed CentralGoogle Scholar
- Fang M, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang C (2003) Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 63:7563–7570PubMedGoogle Scholar
- Fang M, Chen D, Sun Y, Jin Z, Christman J, Yang C (2005) Reversal of hypermethylation and reactivation of p16INK4a, RARbeta, and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res 11:7033–7041PubMedGoogle Scholar
- Fang M, Chen D, Yang C (2007) Dietary polyphenols may affect DNA methylation. J Nutr 137:223S–228SPubMedGoogle Scholar
- Fassina G, Venè R, Morini M, Minghelli S, Benelli R, Noonan D, Albini A (2004) Mechanisms of inhibition of tumor angiogenesis and vascular tumor growth by epigallocatechin-3-gallate. Clin Cancer Res 10:4865–4873PubMedGoogle Scholar
- Fraga M, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer N, Pérez-Rosado A, Calvo E, Lopez J, Cano A, Calasanz M, Colomer D, Piris M, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400PubMedGoogle Scholar
- Fu S, Kurzrock R (2010) Development of curcumin as an epigenetic agent. Cancer (in press)
- Ganesan A, Nolan L, Crabb SJ, Packham G (2009) Epigenetic therapy: histone acetylation, DNA methylation and anti-cancer drug discovery. Curr Cancer Drug Targets 9:963–981PubMedGoogle Scholar
- Gao Z, Xu Z, Hung MS, Lin YC, Wang T, Gong M, Zhi X, Jablon DM, You L (2009) Promoter demethylation of WIF-1 by epigallocatechin-3-gallate in lung cancer cells. Anticancer Res 29:2025–2030PubMedGoogle Scholar
- Görisch S, Wachsmuth M, Tóth K, Lichter P, Rippe K (2005) Histone acetylation increases chromatin accessibility. J Cell Sci 118:5825–5834PubMedGoogle Scholar
- Graham H (1992) Green tea composition, consumption, and polyphenol chemistry. Prev Med 21:334–350PubMedGoogle Scholar
- Grønbaek K, Hother C, Jones P (2007) Epigenetic changes in cancer. APMIS 115:1039–1059PubMedGoogle Scholar
- Gu Y, Zhu CF, Iwamoto H, Chen JS (2005) Genistein inhibits invasive potential of human hepatocellular carcinoma by altering cell cycle, apoptosis, and angiogenesis. World J Gastroenterol 11:6512–6517PubMedPubMed CentralGoogle Scholar
- Gu B, Ding Q, Xia G, Fang Z (2009) EGCG inhibits growth and induces apoptosis in renal cell carcinoma through TFPI-2 overexpression. Oncol Rep 21:635–640PubMedGoogle Scholar
- Guerrero-Bosagna C, Sabat P, Valdovinos F, Valladares L, Clark S (2008) Epigenetic and phenotypic changes result from a continuous pre and post natal dietary exposure to phytoestrogens in an experimental population of mice. BMC Physiol 8:17PubMedPubMed CentralGoogle Scholar
- Guil S, Esteller M (2009) DNA methylomes, histone codes and miRNAs: tying it all together. Int J Biochem Cell Biol 41:87–95PubMedGoogle Scholar
- Guilleret I, Benhattar J (2004) Unusual distribution of DNA methylation within the hTERT CpG island in tissues and cell lines. Biochem Biophys Res Commun 325:1037–1043PubMedGoogle Scholar
- Hebbes T, Thorne A, Crane-Robinson C (1988) A direct link between core histone acetylation and transcriptionally active chromatin. EMBO J 7:1395–1402PubMedPubMed CentralGoogle Scholar
- Hellebrekers D, Griffioen A, van Engeland M (2007) Dual targeting of epigenetic therapy in cancer. Biochim Biophys Acta 1775:76–91PubMedGoogle Scholar
- Herceg Z (2007) Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. Mutagenesis 22:91–103PubMedGoogle Scholar
- Herman-Antosiewicz A, Xiao H, Lew KL, Singh SV (2007) Induction of p21 protein protects against sulforaphane-induced mitotic arrest in LNCaP human prostate cancer cell line. Mol Cancer Ther 6:1673–1681PubMedGoogle Scholar
- Higdon JV, Delage B, Williams DE, Dashwood RH (2007) Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 55:224–236PubMedPubMed CentralGoogle Scholar
- Ho E, Clarke JD, Dashwood RH (2009) Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention. J Nutr 139:2393–2396PubMedPubMed CentralGoogle Scholar
- Holliday R (1990) Mechanisms for the control of gene activity during development. Biol Rev Camb Philos Soc 65:431–471PubMedGoogle Scholar
- Huh S, Bae S, Kim Y, Lee J, Namkoong S, Lee I, Kim S, Kim C, Ahn W (2004) Anticancer effects of (-)-epigallocatechin-3-gallate on ovarian carcinoma cell lines. Gynecol Oncol 94:760–768PubMedGoogle Scholar
- Huo C, Yang H, Cui QC, Dou QP, Chan TH (2010) Proteasome inhibition in human breast cancer cells with high catechol-O-methyltransferase activity by green tea polyphenol EGCG analogs. Bioorg Med Chem 18:1252–1258PubMedPubMed CentralGoogle Scholar
- Issa JP (2008) Cancer prevention: epigenetics steps up to the plate. Cancer Prev Res (Phila Pa) 1:219–222Google Scholar
- Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman E, Caldwell S, Napper A, Curtis R, DiStefano P, Fields S, Bedalov A, Kennedy B (2005) Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 280:17038–17045PubMedGoogle Scholar
- Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh L, Lee S, Leighton J, Patel H, Rahman A, Sridhara R, Wang Y, Pazdur R, FDA (2005) Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11:3604–3608PubMedGoogle Scholar
- Kang SK, Cha SH, Jeon HG (2006) Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev 15:165–174PubMedGoogle Scholar
- Kanwar J, Mohammad I, Yang H, Huo C, Chan TH, Dou QP (2010) Computational modeling of the potential interactions of the proteasome beta5 subunit and catechol-O-methyltransferase-resistant EGCG analogs. Int J Mol Med 26:209–215PubMedPubMed CentralGoogle Scholar
- Kato K, Long NK, Makita H, Toida M, Yamashita T, Hatakeyama D, Hara A, Mori H, Shibata T (2008) Effects of green tea polyphenol on methylation status of RECK gene and cancer cell invasion in oral squamous cell carcinoma cells. Br J Cancer 99:647–654PubMedPubMed CentralGoogle Scholar
- Keum YS, Khor TO, Lin W, Shen G, Kwon KH, Barve A, Li W, Kong AN (2009) Pharmacokinetics and pharmacodynamics of broccoli sprouts on the suppression of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: implication of induction of Nrf2, HO-1 and apoptosis and the suppression of Akt-dependent kinase pathway. Pharm Res 26:2324–2331PubMedGoogle Scholar
- Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Majid S, Igawa M, Dahiya R (2008) Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells. Int J Cancer 123:552–560PubMedGoogle Scholar
- Kim D, Kim M, Kwon H (2003) Histone deacetylase in carcinogenesis and its inhibitors as anti-cancer agents. J Biochem Mol Biol 36:110–119PubMedGoogle Scholar
- King-Batoon A, Leszczynska J, Klein C (2008) Modulation of gene methylation by genistein or lycopene in breast cancer cells. Environ Mol Mutagen 49:36–45PubMedGoogle Scholar
- Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705PubMedGoogle Scholar
- Kraft TE, Parisotto D, Schempp C, Efferth T (2009) Fighting cancer with red wine? Molecular mechanisms of resveratrol. Crit Rev Food Sci Nutr 49:782–799PubMedGoogle Scholar
- Lafon-Hughes L, Di Tomaso M, Méndez-Acuña L, Martínez-López W (2008) Chromatin-remodelling mechanisms in cancer. Mutat Res 658:191–214PubMedGoogle Scholar
- Laird P (2005) Cancer epigenetics. Hum Mol Genet 14(Spec No 1):R65–R76PubMedGoogle Scholar
- Landis-Piwowar KR, Huo C, Chen D, Milacic V, Shi G, Chan TH, Dou QP (2007) A novel prodrug of the green tea polyphenol (-)-epigallocatechin-3-gallate as a potential anticancer agent. Cancer Res 67:4303–4310PubMedGoogle Scholar
- Landis-Piwowar KR, Milacic V, Dou QP (2008) Relationship between the methylation status of dietary flavonoids and their growth-inhibitory and apoptosis-inducing activities in human cancer cells. J Cell Biochem 105:514–523PubMedPubMed CentralGoogle Scholar
- Landis-Piwowar K, Chen D, Chan TH, Dou QP (2010) Inhibition of catechol-Omicron-methyltransferase activity in human breast cancer cells enhances the biological effect of the green tea polyphenol (-)-EGCG. Oncol Rep 24:563–569PubMedPubMed CentralGoogle Scholar
- Lea M, Randolph V, Lee J, desBordes C (2001) Induction of histone acetylation in mouse erythroleukemia cells by some organosulfur compounds including allyl isothiocyanate. Int J Cancer 92:784–789PubMedGoogle Scholar
- Lee W, Zhu B (2006) Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two common catechol-containing coffee polyphenols. Carcinogenesis 27:269–277PubMedGoogle Scholar
- Lee S, Lee H, Kim J, Lee H, Jang J, Kang G (2003) Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 163:1371–1378PubMedPubMed CentralGoogle Scholar
- Lee W, Shim J, Zhu B (2005) Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol 68:1018–1030PubMedGoogle Scholar
- Li Y, Tollefsbol T (2010) Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr Med Chem 17:2141–2151PubMedPubMed CentralGoogle Scholar
- Li LH, Wu LJ, Tashiro SI, Onodera S, Uchiumi F, Ikejima T (2007) Activation of the SIRT1 pathway and modulation of the cell cycle were involved in silymarin's protection against UV-induced A375-S2 cell apoptosis. J Asian Nat Prod Res 9:245–252PubMedGoogle Scholar
- Li H, Liu C, de Couto G, Ouzounian M, Sun M, Wang A, Huang Y, He C, Shi Y, Chen X, Nghiem M, Liu Y, Chen M, Dawood F, Fukuoka M, Maekawa Y, Zhang L, Leask A, Ghosh A, Kirshenbaum L, Liu P (2008) Curcumin prevents and reverses murine cardiac hypertrophy. J Clin Invest 118:879–893PubMedPubMed CentralGoogle Scholar
- Li Y, Liu L, Andrews LG, Tollefsbol TO (2009a) Genistein depletes telomerase activity through cross-talk between genetic and epigenetic mechanisms. Int J Cancer 125:286–296PubMedPubMed CentralGoogle Scholar
- Li Y, VandenBoom Tn, Kong D, Wang Z, Ali S, Philip P, Sarkar F (2009b) Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 69:6704–6712PubMedPubMed CentralGoogle Scholar
- Li Y, Liu L, Tollefsbol TO (2010) Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J 24:1442–1453PubMedPubMed CentralGoogle Scholar
- Liang G, Tang A, Lin X, Li L, Zhang S, Huang Z, Tang H, Li QQ (2010) Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int J Oncol 37:111–123PubMedGoogle Scholar
- Lin J, Liang Y (2000) Cancer chemoprevention by tea polyphenols. Proc Natl Sci Counc Repub China B 24:1–13PubMedGoogle Scholar
- Liu H, Chen Y, Cui G, Zhou J (2005) Curcumin, a potent anti-tumor reagent, is a novel histone deacetylase inhibitor regulating B-NHL cell line Raji proliferation. Acta Pharmacol Sin 26:603–609PubMedGoogle Scholar
- Liu PL, Tsai JR, Charles AL, Hwang JJ, Chou SH, Ping YH, Lin FY, Chen YL, Hung CY, Chen WC, Chen YH, Chong IW (2010) Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases. Mol Nutr Food Res 54:S196–S204PubMedGoogle Scholar
- Majid S, Kikuno N, Nelles J, Noonan E, Tanaka Y, Kawamoto K, Hirata H, Li L, Zhao H, Okino S, Place R, Pookot D, Dahiya R (2008) Genistein induces the p21WAF1/CIP1 and p16INK4a tumor suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modification. Cancer Res 68:2736–2744PubMedGoogle Scholar
- Majid S, Dar AA, Ahmad AE, Hirata H, Kawakami K, Shahryari V, Saini S, Tanaka Y, Dahiya AV, Khatri G, Dahiya R (2009) BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer. Carcinogenesis 30:662–670PubMedPubMed CentralGoogle Scholar
- Mao QQ, Bai Y, Lin YW, Zheng XY, Qin J, Yang K, Xie LP (2010) Resveratrol confers resistance against taxol via induction of cell cycle arrest in human cancer cell lines. Mol Nutr Food Res (in press)
- Marcu MG, Jung YJ, Lee S, Chung EJ, Lee MJ, Trepel J, Neckers L (2006) Curcumin is an inhibitor of p300 histone acetylatransferase. Med Chem 2:169–174PubMedGoogle Scholar
- Marsoni S, Damia G, Camboni G (2008) A work in progress: the clinical development of histone deacetylase inhibitors. Epigenetics 3:164–171PubMedGoogle Scholar
- Meeran S, Katiyar S (2008) Cell cycle control as a basis for cancer chemoprevention through dietary agents. Front Biosci 13:2191–2202PubMedPubMed CentralGoogle Scholar
- Meeran S, Patel S, Tollefsbol T (2010) Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. PLoS ONE 5:e11457PubMedPubMed CentralGoogle Scholar
- Meja K, Rajendrasozhan S, Adenuga D, Biswas S, Sundar I, Spooner G, Marwick J, Chakravarty P, Fletcher D, Whittaker P, Megson I, Kirkham P, Rahman I (2008) Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol 39:312–323PubMedPubMed CentralGoogle Scholar
- Mittal A, Piyathilake C, Hara Y, Katiyar S (2003) Exceptionally high protection of photocarcinogenesis by topical application of (–)-epigallocatechin-3-gallate in hydrophilic cream in SKH-1 hairless mouse model: relationship to inhibition of UVB-induced global DNA hypomethylation. Neoplasia 5:555–565PubMedPubMed CentralGoogle Scholar
- Moiseeva EP, Almeida GM, Jones GD, Manson MM (2007) Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol Cancer Ther 6:3071–3079PubMedGoogle Scholar
- Mottet D, Castronovo V (2008) Histone deacetylases: target enzymes for cancer therapy. Clin Exp Metastasis 25:183–189PubMedGoogle Scholar
- Morey Kinney SR, Zhang W, Pascual M, Greally JM, Gillard BM, Karasik E, Foster BA, Karpf AR (2009) Lack of evidence for green tea polyphenols as DNA methylation inhibitors in murine prostate. Cancer Prev Res (Phila Pa) 2:1065–1075Google Scholar
- Morimoto T, Sunagawa Y, Kawamura T, Takaya T, Wada H, Nagasawa A, Komeda M, Fujita M, Shimatsu A, Kita T, Hasegawa K (2008) The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin Invest 118:868–878PubMedPubMed CentralGoogle Scholar
- Mukhtar H, Ahmad N (2000) Tea polyphenols: prevention of cancer and optimizing health. Am J Clin Nutr 71:1698S–1702S, discussion 1703S-1694SPubMedGoogle Scholar
- Murugan RS, Vinothini G, Hara Y, Nagini S (2009) Black tea polyphenols target matrix metalloproteinases, RECK, proangiogenic molecules and histone deacetylase in a rat hepatocarcinogenesis model. Anticancer Res 29:2301–2305PubMedGoogle Scholar
- Myzak MC, Karplus PA, Chung FL, Dashwood RH (2004) A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res 64:5767–5774PubMedGoogle Scholar
- Myzak MC, Dashwood WM, Orner GA, Ho E, Dashwood RH (2006a) Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc-minus mice. FASEB J 20:506–508PubMedPubMed CentralGoogle Scholar
- Myzak MC, Hardin K, Wang R, Dashwood RH, Ho E (2006b) Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis 27:811–819PubMedPubMed CentralGoogle Scholar
- Myzak M, Ho E, Dashwood R (2006c) Dietary agents as histone deacetylase inhibitors. Mol Carcinog 45:443–446PubMedPubMed CentralGoogle Scholar
- Myzak MC, Tong P, Dashwood WM, Dashwood RH, Ho E (2007) Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects. Exp Biol Med (Maywood) 232:227–234Google Scholar
- Nair S, Hebbar V, Shen G, Gopalakrishnan A, Khor TO, Yu S, Xu C, Kong AN (2008) Synergistic effects of a combination of dietary factors sulforaphane and (-) epigallocatechin-3-gallate in HT-29 AP-1 human colon carcinoma cells. Pharm Res 25:387–399PubMedGoogle Scholar
- Nian H, Delage B, Ho E, Dashwood R (2009) Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds. Environ Mol Mutagen 50:213–221PubMedPubMed CentralGoogle Scholar
- Nihal M, Roelke CT, Wood GS (2010) Anti-melanoma effects of vorinostat in combination with polyphenolic antioxidant (-)-epigallocatechin-3-gallate (EGCG). Pharm Res 27:1103–1114PubMedGoogle Scholar
- Paluszczak J, Krajka-Kuzniak V, Baer-Dubowska W (2010) The effect of dietary polyphenols on the epigenetic regulation of gene expression in MCF7 breast cancer cells. Toxicol Lett 192:119–125PubMedGoogle Scholar
- Pandey M, Shukla S, Gupta S (2010) Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells. Int J Cancer 126:2520–2533PubMedPubMed CentralGoogle Scholar
- Papoutsis AJ, Lamore SD, Wondrak GT, Selmin OI, Romagnolo DF (2010) Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells. J Nutr 140(9):1607–1614PubMedPubMed CentralGoogle Scholar
- Parker L, Taylor D, Kesterson J, Metzinger D, Gercel-Taylor C (2009) Modulation of microRNA associated with ovarian cancer cells by genistein. Eur J Gynaecol Oncol 30:616–621PubMedGoogle Scholar
- Pledgie-Tracy A, Sobolewski MD, Davidson NE (2007) Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther 6:1013–1021PubMedGoogle Scholar
- Plummer R, Vidal L, Griffin M, Lesley M, de Bono J, Coulthard S, Sludden J, Siu L, Chen E, Oza A, Reid G, McLeod A, Besterman J, Lee C, Judson I, Calvert H, Boddy A (2009) Phase I study of MG98, an oligonucleotide antisense inhibitor of human DNA methyltransferase 1, given as a 7-day infusion in patients with advanced solid tumors. Clin Cancer Res 15:3177–3183PubMedGoogle Scholar
- Pollack BP, Sapkota B, Boss JM (2009) Ultraviolet radiation-induced transcription is associated with gene-specific histone acetylation. Photochem Photobiol 85:652–662PubMedGoogle Scholar
- Qin W, Zhu W, Shi H, Hewett JE, Ruhlen RL, MacDonald RS, Rottinghaus GE, Chen YC, Sauter ER (2009) Soy isoflavones have an antiestrogenic effect and alter mammary promoter hypermethylation in healthy premenopausal women. Nutr Cancer 61:238–244PubMedPubMed CentralGoogle Scholar
- Quante M, Heeg S, von Werder A, Goessel G, Fulda C, Doebele M, Nakagawa H, Beijersbergen R, Blum H, Opitz O (2005) Differential transcriptional regulation of human telomerase in a cellular model representing important genetic alterations in esophageal squamous carcinogenesis. Carcinogenesis 26:1879–1889PubMedGoogle Scholar
- Raynal NJ, Charbonneau M, Momparler LF, Momparler RL (2008) Synergistic effect of 5-Aza-2'-deoxycytidine and genistein in combination against leukemia. Oncol Res 17:223–230PubMedGoogle Scholar
- Reuter S, Eifes S, Dicato M, Aggarwal BB, Diederich M (2008) Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem Pharmacol 76:1340–1351PubMedGoogle Scholar
- Sagara Y, Miyata Y, Nomata K, Hayashi T, Kanetake H (2010) Green tea polyphenol suppresses tumor invasion and angiogenesis in N-butyl-(-4-hydroxybutyl) nitrosamine-induced bladder cancer. Cancer Epidemiol 34:350–354PubMedGoogle Scholar
- Saito Y, Jones P (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5:2220–2222PubMedGoogle Scholar
- Sasamura H, Takahashi A, Yuan J, Kitamura H, Masumori N, Miyao N, Itoh N, Tsukamoto T (2004) Antiproliferative and antiangiogenic activities of genistein in human renal cell carcinoma. Urology 64:389–393PubMedGoogle Scholar
- Seligson D, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani S (2005) Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435:1262–1266PubMedGoogle Scholar
- Shanafelt T, Call T, Zent C, LaPlant B, Bowen D, Roos M, Secreto C, Ghosh A, Kabat B, Lee M, Yang C, Jelinek D, Erlichman C, Kay N (2009) Phase I trial of daily oral polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia. J Clin Oncol 27:3808–3814PubMedPubMed CentralGoogle Scholar
- Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36PubMedPubMed CentralGoogle Scholar
- Shishodia S, Chaturvedi M, Aggarwal B (2007) Role of curcumin in cancer therapy. Curr Probl Cancer 31:243–305PubMedGoogle Scholar
- Singh AV, Franke AA, Blackburn GL, Zhou JR (2006) Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis. Cancer Res 66:1851–1858PubMedPubMed CentralGoogle Scholar
- Stefanska B, Rudnicka K, Bednarek A, Fabianowska-Majewska K (2010) Hypomethylation and induction of retinoic acid receptor beta 2 by concurrent action of adenosine analogues and natural compounds in breast cancer cells. Eur J Pharmacol 638:47–53PubMedGoogle Scholar
- Su SJ, Yeh TM, Chuang WJ, Ho CL, Chang KL, Cheng HL, Liu HS, Hsu PY, Chow NH (2005) The novel targets for anti-angiogenesis of genistein on human cancer cells. Biochem Pharmacol 69:307–318PubMedGoogle Scholar
- Sun Q, Cong R, Yan H, Gu H, Zeng Y, Liu N, Chen J, Wang B (2009) Genistein inhibits growth of human uveal melanoma cells and affects microRNA-27a and target gene expression. Oncol Rep 22:563–567PubMedGoogle Scholar
- Suter M, Aagaard-Tillery K (2009) Environmental influences on epigenetic profiles. Semin Reprod Med 27:380–390PubMedGoogle Scholar
- Tang W, Newbold R, Mardilovich K, Jefferson W, Cheng R, Medvedovic M, Ho S (2008) Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology 149:5922–5931PubMedPubMed CentralGoogle Scholar
- Tate P, Bird A (1993) Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev 3:226–231PubMedGoogle Scholar
- Telang U, Brazeau D, Morris M (2009) Comparison of the effects of phenethyl isothiocyanate and sulforaphane on gene expression in breast cancer and normal mammary epithelial cells. Exp Biol Med (Maywood) 234:287–295Google Scholar
- Tikoo K, Meena R, Kabra D, Gaikwad A (2008) Change in post-translational modifications of histone H3, heat-shock protein-27 and MAP kinase p38 expression by curcumin in streptozotocin-induced type I diabetic nephropathy. Br J Pharmacol 153:1225–1231PubMedPubMed CentralGoogle Scholar
- Traka M, Gasper A, Smith J, Hawkey C, Bao Y, Mithen R (2005) Transcriptome analysis of human colon Caco-2 cells exposed to sulforaphane. J Nutr 135:1865–1872PubMedGoogle Scholar
- Tran PL, Kim SA, Choi HS, Yoon JH, Ahn SG (2010) Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo. BMC Cancer 10:276PubMedPubMed CentralGoogle Scholar
- Tsao A, Liu D, Martin J, Tang X, Lee J, El-Naggar A, Wistuba I, Culotta K, Mao L, Gillenwater A, Sagesaka Y, Hong W, Papadimitrakopoulou V (2009) Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila Pa) 2:931–941Google Scholar
- Vanamala J, Reddivari L, Radhakrishnan S, Tarver C (2010) Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways. BMC Cancer 10:238PubMedPubMed CentralGoogle Scholar
- Volate SR, Muga SJ, Issa AY, Nitcheva D, Smith T, Wargovich MJ (2009) Epigenetic modulation of the retinoid X receptor alpha by green tea in the azoxymethane-Apc Min/+ mouse model of intestinal cancer. Mol Carcinog 48:920–933PubMedPubMed CentralGoogle Scholar
- Wade P (2001) Methyl CpG-binding proteins and transcriptional repression. Bioessays 23:1131–1137PubMedGoogle Scholar
- Wang R, Zheng Y, Kim H, Xu X, Cao L, Luhasen T, Lee M, Xiao C, Vassilopoulos A, Chen W, Gardner K, Man Y, Hung M, Finkel T, Deng C (2008) Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell 32:11–20PubMedPubMed CentralGoogle Scholar
- Yang C, Landau J, Huang M, Newmark H (2001) Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr 21:381–406PubMedGoogle Scholar
- Yuasa Y, Nagasaki H, Akiyama Y, Sakai H, Nakajima T, Ohkura Y, Takizawa T, Koike M, Tani M, Iwai T, Sugihara K, Imai K, Nakachi K (2005) Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients. Carcinogenesis 26:193–200PubMedGoogle Scholar
- Yuasa Y, Nagasaki H, Akiyama Y, Hashimoto Y, Takizawa T, Kojima K, Kawano T, Sugihara K, Imai K, Nakachi K (2009) DNA methylation status is inversely correlated with green tea intake and physical activity in gastric cancer patients. Int J Cancer 124:2677–2682PubMedGoogle Scholar
- Yun JM, Jialal I, Devaraj S (2010a) Effects of epigallocatechin gallate on regulatory T cell number and function in obese v. lean volunteers. Br J Nutr 103:1771–1777PubMedGoogle Scholar
- Yun JM, Jialal I, Devaraj S (2010b) Epigenetic regulation of high glucose-induced proinflammatory cytokine production in monocytes by curcumin. J Nutr Biochem (in press)
- Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Sharan C, Rajaratnam V, Khurana A, Al-Hendy A (2010) Green tea extract inhibits proliferation of uterine leiomyoma cells in vitro and in nude mice. Am J Obstet Gynecol 202(289):e281–e289Google Scholar