Green tea, olive oil, blueberries, garlic and broccoli are among foods that work to reverse epigenetic changes that create susceptibility to cancers. A number of recent research publications relate to complex epigenetic conditions that lead to cancers – conditions that typically involve DNA methylation and histone acetylation.  A number of other recent publications point out how many of these conditions are reversible via dietary inputs of substances that are old friends to many of my readers – substances like olive oil, blueberries, garlic, green tea, curcumin and resveratrol.  Indeed, this new research is providing deep insight into why certain dietary polyphenols are effective in preventing cancers via their epigenetic actions.  After a little background, I quote relevant passages from a number of these publications. 

Background: Plant polyphenols and cancer

We have long known from large population studies that regular consumption of certain dietary substances and supplements like green tea, olive oil, blueberries, oregano, ginger and hot chili peppers can negatively impact on incidences of cancer.  We also know from multiple studies that certain plant-based polyphenol substances like rosmarinic acid, curcumin, lycopene, caffeic acid, resveratrol and gingerol inhibit the development of certain cancers.  Indeed this research has been the basis for my suggested lifestyle  and dietary supplement anti-aging regimens.  The October 2009 blog entry Nrf2 and cancer chemoprevention by phytochemicals  provides a specialized but interesting introduction to the topic of cancer chemoprevention by certain dietary substances.  It also lists a number of literature citations on this subject.  The present blog entry goes into the basic epigenetic mechanisms involved. 

Background: Epigenetics of cancer

The December 2010 blog entry Epigenetics of cancer and aging provides a well-focused introduction to and explanation of this topic for readers.  It also contains numerous links to relevant previous blog entries and research publications.  This current blog entry picks up where that one leaves off. 

Epigenetic mechanisms of dietary substances  that avert cancers 

Getting to the main meat of this blog post, a good place to start is with the December 2010 publication Epigenetic targets of bioactive dietary components for cancer prevention and therapy.  “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 –.  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 p21WAF1/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. — 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.”  

The basic concepts here are simple:

1.                 Cancers and cancer growth are facilitated by or caused by environmentally-conditioned and possibly inheritable epigenetic modifications, and

2.                 Many such epigenetic modifications are reversible by selected dietary inputs.  The genome is programmed by the epigenome and the epigenome in turn is largely programmed by the social and physical environment(ref)(ref).

“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(ref).”  Further, “The link of lifestyles, such as dietary patterns and physical activity, to the risk of developing cancer and other diseases has received support from a plethora of epidemiological and biochemical studies. In line with this, a report from the World Health Organization (WHO) states that cancer causes 7.1 million deaths annually (12.5% of the global total) and dietary factors account for about 30% of all cancers in western countries and approximately up to 20% in developing countries(ref).” 

Among numerous other factors affecting the epigenetic-related risks of cancers are insufficient exercise, smoking and exposure to environmental toxins.  And reversible epigenetic changes can lead to other disease and degenerative processes.  For example, some pesticides in the environment work to cause neuron loss via histone acetylation, as pointed out in the 2010 publication Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration. 

“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).” [You can also see my blog entries MicroRNAs in cancers and aging and MicroRNAs, diseases and yet-another view of aging.]  “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)(ref).”

DNA methylation

The 2010 publication Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components relates “It is well established that aberrant gene regulation by epigenetic mechanisms can develop as a result of pathological processes such as cancer. Methylation of CpG islands is an important component of the epigenetic code and a number of genes become abnormally methylated during tumorigenesis.”  These include tumor suppressor genes like p16/INK4a, turning them off(ref).  Continuing, “Some bioactive food components have been shown to have cancer inhibition activities by reducing DNA hypermethylation of key cancer-causing genes through their DNA methyltransferase (DNMT) inhibition properties. The dietary polyphenols, (-)-epigallocatechin- 3-gallate (EGCG) from green tea, genistein from soybean and possibly isothiocyanates from plant foods, are some examples of these bioactive food components modulated by epigenetic factors. The activity of cancer inhibition generated from dietary polyphenols is associated with gene reactivation through demethylation in the promoters of methylation-silenced genes such as p16INK4a and retinoic acid receptor beta. The effects of dietary polyphenols such as EGCG on DNMTs appear to have their direct inhibition by interaction with the catalytic site of the DNMT1 molecule, and may also influence methylation status indirectly through metabolic effects associated with energy metabolism. Therefore, reversal of hypermethylation-induced inactivation of key tumor suppression genes by dietary DNMT inhibitors could be an effective approach to cancer prevention and therapy(ref).”

In more detail “DNA methylation, occurring primarily at cytosine-guanine (CpG) dinucleotides, is a heritable, tissue- and species-specific modification of mammalian DNA [5, 6]. CpG dinucleotides are frequently clustered into CpG islands, regions that are rich in CpG sites. These islands extend about 0.5–3 Kb, occur on average every 100 Kb in the genome and are found in approximately half of all genes in humans [7]. DNA methylation often occurs at the regulatory sites of gene promoter regions and involves an enzymatic process by addition of a methyl group to the 5-position of the cytosine ring of CpG dinucleotides (Fig. 1). It is an important epigenetic determinant in gene expression, maintenance of DNA integrity and stability in many biological processes such as genomic imprinting, normal development and proliferation [8–10]. DNA hypermethylation of CpG islands is usually associated with silencing of the expression of genes in contrast to loss of methylation which often leads to gene reactivation. Abnormal patterns of DNA methylation may ultimately lead to genetic instability and cancer development through epigenetic inactivation of certain critical cancer-related genes by promoter hypermethylation [11] (Fig. 1). These altered genes include tumor suppressor genes, such as the cell cycle checkpoint genes, p21^WAF1/CIP1 and p16 ^INK4a, and growth regulatory genes, such as RAS association domain family 1A (RASSF1A) and retinoic acid receptor β (RARβ). Furthermore, promoter hypomethylation-induced oncogene activation contributes to the processes of tumorigenesis [12]. Aberrant DNA methylation occurs at specific genes in almost all neoplasms, suggesting that this alteration may be a molecular marker in cancer prevention and therapeutic approaches(ref).”

Continuing, – “Numerous studies have demonstrated that certain dietary components inhibit cancer proliferation by affecting epigenetic signaling pathways both in vitro and in vivo [37, 38]. The green tea polyphenol, EGCG, is believed to be a key active ingredient for cancer inhibition through epigenetic control. It has been found that EGCG can reverse CpG island hypermethylation of various methylation-silenced genes and reactivate these gene expressions through inhibition of DNMT1 enzymatic activity [39]. Moreover, EGCG has been proposed to regulate gene expression through the mechanism of chromatin remodeling suggesting that EGCG could exert its anticancer ability through both epigenetic mechanisms. Another well-known bioactive dietary compound is the soybean isoflavone, genistein, which has also been found to inhibit tumorigenesis through epigenetic control in several cancer cell lines [40, 41](ref).”

Lysine(K) acetylation

Another related set of mechanisms by which dietary substances affect epigenomics so as to prevent cancers involves lysine (K) acetylation.  The October 2010 e-publication Dietary, metabolic, and potentially environmental modulation of the lysine acetylation machinery reports: “Epigenetic changes play a key role in defining gene expression patterns under both normal and pathological conditions. As a major posttranslational modification, lysine (K) acetylation has received much attention, owing largely to its significant effects on chromatin dynamics and other cellular processes across species. Lysine acetyltransferases and deacetylases, two opposing families of enzymes governing K-acetylation, have been intimately linked to cancer and other diseases. These enzymes have been pursued by vigorous efforts for therapeutic development in the past 15 years or so. Interestingly, certain dietary components have been found to modulate acetylation levels in vivo. Here we review dietary, metabolic, and environmental modulators of the K-acetylation machinery and discuss how they may be of potential value in the context of disease prevention.” 

“As a key component of the epigenetic makeup, lysine acetylation is now recognized as one fundamental posttranslational modification exerting profound effects on chromatin dynamics and other cellular processes in different species [2–4]. This modification transfers the acetyl moiety from acetyl-CoA to the ε-group of a lysine residue (Figure 1), which is reversible and dynamically governed by two groups of counteracting enzymes known as lysine acetyltransferases (KATs) and deacetylases (KDACs) [5–7]. Due to historical reasons, KDACs have almost exclusively been referred to HDACs (histone deacetylases), –.   Acetylation of specific lysine residues on histones is generally associated with transcriptional activation, whereas histone deacetylation results in transcriptional repression [8, 9](ref).”

At least one acetyltransferase is a longevity factor required for calorie restriction-mediated life span extension(ref).

In earlier blog entries I have related how inhibition of expression of NF-kappaB is a mechanism through which a number of phytochemicals like curcumin and resveratrol work to inhibit cancers(ref)(ref).  The 2010 publication Acetylation of p65 at lysine 314 is important for late NF-k(kappa)B-dependent gene expression links (K) acetylation to inhibition of NF-kappaB.  “BACKGROUND: NF-k(kappa)B regulates the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation and survival. We have earlier reported that p65, a subunit of NF-k(kappa)B, is acetylated in vitro and in vivo at three different lysines (K310, K314 and K315) by the histone acetyltransferase p300. RESULTS: In this study, we describe that site-specific mutation of p65 at lysines 314 and 315 enhances gene expression of a subset of NF-k(kappa)B target genes including Mmp10 and Mmp13. Increased gene expression was mainly observed three hours after TNFa(alpha) stimulation. Chromatin immunoprecipitation (ChIP) experiments with an antibody raised against acetylated lysine 314 revealed that chromatin-bound p65 is indeed acetylated at lysine 314. CONCLUSIONS: Together, our results establish acetylation of K314 as an important regulatory modification of p65 and subsequently of NF-k(kappa)B-dependent gene expression.” 

Relevant to this last factor and the subject of this post, I remind my readers that 39 of the supplements in my Anti-Aging Firewalls regimen are inhibitors of NF-kappaB expression or binding.  It is likely that (K) acetylation plays a key role in the actions of many if not all of these.

“Delicate control is required for maintaining an appropriate acetylation profile for normal cellular functions. An imbalance has been associated with various diseases. As a result, many KAT and HDAC inhibitors, as well as activators, have emerged as promising agents for modulating this modification and treating diseases whose roots originate from altered K-acetylation. Several HDAC inhibitors have received approval from the US Food and Drug Administration (FDA) for treating cutaneous T-cell lymphoma [20]. In addition, scientists have discovered that some dietary components modulate KAT and HDAC activities (Figure 2), and have analyzed lifestyles to determine factors that may influence the functioning of these enzymes](ref).”  For example, resveratrol is a HDAC inhibitor(ref).

Interestingly, HDAC inhibitors can provide a number of other health effects.  For example, they can serve as anti-depressants(ref) and can be used to enhance learning and memory following traumatic brain injury(ref).

Epigenetic activities of specific cancer-inhibiting foods

This table relates dietary components that inhibit cancer to their epigenetic activities, lists target genes and research references.  The table is from the publicationmentioned earlier Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components .  This paper explains the key epigenetic roles of the DNMT methyltransferases, and details how several classes of food chemicals operate on an epigenetic level to inhibit cancers.  It has sections describing  the epigenetic anti-cancer activities of Tea polyphenols, Soy isoflavone genistein, Other polyphenols, Selenium, and Isothiocynates.  I comment here only selectively on the actions of some of these and other selected dietary compounds.

Isothiocyanates and allyl compounds

“Isothiocyanates, metabolites of glucosinolates, are found naturally in cruciferous vegetables, such as broccoli, cabbages, and watercress and have been reported to reduce the incidence of prostate cancer (Table 2) [99]. Phenethyl isothiocyanate (PEITC), a hydrolytic product of glucosinolate gluconasturtin, has been proposed to reduce cell growth of prostate cancer both in vivo and in vitro [100, 101].”

The 2009 publication Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds reports. “– Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic.  Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention.”

Resveratrol

The 2010 publication Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex describes a mechanism by which resveratrol acetylates and therefore turns on the apoptosis gene P53 gene in cancer cells to kill them.

More relevant publications

Among of the other recent publications relevant to this blog entry are

·        Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells.

·        The dietary histone deacetylase inhibitor sulforaphane induces human β-defensin-2 in intestinal epithelial cells·        Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines

·        Dietary sulforaphane, a histone deacetylase inhibitor for cancer prevention

·        Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds.

·        A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase

·         Dietary agents as histone deacetylase inhibitors

·        Sulforaphane destabilizes the androgen receptor in prostate cancer cells by inactivating histone deacetylase 

·        Synergistic effects of a combination of dietary factors sulforaphane and (-) epigallocatechin-3-gallate in HT-29 AP-1 human colon carcinoma cells

·         Histone deacetylases as targets for dietary cancer preventive agents: lessons learned with butyrate, diallyl disulfide, and sulforaphane

·        Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter

·        Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? 

·        Cancer-preventive peptide lunasin from Solanum nigrum L. inhibits acetylation of core histones H3 and H4 and phosphorylation of retinoblastoma protein (Rb)

·        The cancer preventive peptide lunasin from wheat inhibits core histone acetylation

·        Inhibition of core histone acetylation by the cancer preventive peptide lunasin

·        Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription

·        Cytotoxic benzophenone derivatives from Garcinia species display a strong apoptosis-inducing effect against human leukemia cell lines

·        Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells

·        Curcumin-induced histone hypoacetylation: the role of reactive oxygen species

·        Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression 

·        Inhibition of lysine acetyltransferase KAT3B/p300 activity by a naturally occurring hydroxynaphthoquinone, plumbagin 

I could go on with this list, and there are many other relevant publications.  You can hyperlink out from these links to a number of others.  The subject of epigenetic dietary interventions to prevent cancers is very hot. 

As usual I am afraid that I have just scratched the surface in this blog entry.  Systematic epigenomic changes appear to be associated with far-flung health issues such as chronic alcohol consumption(ref)(ref) and cocaine addiction(ref).   In fact, epigenomics is emerging as a powerful new lens for looking at all our disease processes and aging.   So, I expect to be writing ever-more blog entries relating to epigenomics.  And, if you are a regular reader of this blog, you already know that one of my most-favorite theories of aging is Programmed Epigenomic Changes.