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Epigenetic diet phytochemicals affecting the epigenome
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- Dietary polyphenols
- Tea polyphenols
- Resveratrol
- Curcumin
- Isoflavones (genistein)
- Isothiocyanates
Epigenetic diet phytochemicals affecting the epigenomeDietary factors play a role in many normal biological processes and are also involved in the regulation of pathological progressions. Diseases linked to genetic and epigenetic modifications can be influenced by environmental and dietary factors. In particular, nutritional factors, drugs, chemicals used in pesticides, environmental compounds and inorganic contaminants (i.e., arsenic) can alter the epigenome, and may contribute to the development of abnormalities [62–66]. It has become increasingly clear that environmentally induced epigenetic changes can be mediated, in part, by diet [67–69]. This is especially illustrated by an early investigation conducted in an animal model, which demonstrated that dietary methyl deficiency of folate, choline and methionine altered DNA methylation patterns in the liver and induced hepatocarcinoma [70]. Evidence has also emerged indicating that giving mice that have developed methyl-deficiency-induced hepatocarcinoma a methyl-sufficient diet can lessen the occurrence of abnormal DNA methylation [71]. Because epigenetic variation can be influenced by dietary factors, it is reasonable to believe that investigating strategies that utilize dietary compounds to target epigenetic modifications may be worthwhile in preventing and treating diseases including cancer. Dietary polyphenolsPolyphenols are present in fruits and vegetables and are a vital part of the human diet [56,72]. Plant polyphenols can be divided into at least ten different classes based on their chemical structure. These classes include: flavonoids, stilbenes, phenolic acids, benzoquinones, acetophenones, lignins and xanthones [72,73]. Polyphenols can range from simple molecules to highly complex compounds and are derived from either phenylalanine (a phenol intermediate) or its precursor shikimic acid. They typically contain one or more sugar residues linked to a hydroxyl group and occur in a conjugated form [72]. Some estimate that more than 8000 distinct dietary polyphenols exist [72]. Examples of common polyphenols include (−)-epigallocatechin-3-gallate (EGCG; found in green tea), curcumin (found in curry) and resveratrol (found in grapes). These dietary polyphenols have a protective role against diseases and also have a significant impact on cancer prevention [74,75]. In fact, various mechanisms have been identified that help to explain the preventive nature of polyphenols, including their ability to alter the epigenome in cancer cells by chromatin remodeling or by reactivating silenced genes [76–78]. The chemo-preventative potential of dietary polyphenols can be traced to their ability to inhibit DNMTs as well as their ability to act as histone modifiers. Both of these properties of dietary polyphenols can significantly change the epigenome of cancer cells and are viewed as attractive possibilities for anticancer therapeutics. Tea polyphenolsNext to water, tea is the most consumed beverage worldwide with approximately 20 billion cups consumed daily [79]. The three most popular types of tea (green, black and oolong) are differentiated based on the degree of fermentation they undergo. Green tea leaves are dried and roasted but not fermented, whereas black tea leaves are well fermented and oolong tea leaves are only partially fermented [79,80]. Studies have indicated that compounds present in tea may reduce the risk of diseases including cancer. Teas contain polyphenolic compounds that serve to protect plants from photosynthetic stressors, reactive oxygen species and consumption by herbivores [56]. As previously stated, polyphenolic compounds in tea may actively reduce the risk of diseases such as cancer. One subcategory of polyphenols, catechins, is the most abundant of the bioactive compounds in green tea. These include (−)-epicatechin (EC), (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC), and EGCG [81]. While all of the aforementioned catechins have been found to share similar properties, the most efficient of these compounds in targeting factors like DNMTs is EGCG [77,78]. EGCG accounts for more than 50% of the active compounds in green tea and has been extensively studied for its anticarcinogenic properties [82]. While studies conducted by Chuang et al. report disagreeing results regarding the effects of EGCG on DNA methylation [83], an increasing number of investigations have suggested a positive correlation between the consumption of EGCG and the inhibition of oral, breast, prostate, gastric, ovarian, esophageal, skin, colorectal, pancreatic, and head and neck cancers [83–88]. Epigallocatechin-3-gallate is thought to exert its anticancer effects through several different mechanisms much of which can be altered by epigenetic mechanisms; these include the induction of apoptosis and cell cycle arrest, inhibition of oxidative stress and angiogenesis, regulation of signal transduction and reduction of cancer cell proliferation [89–92]. EGCG can inhibit DNMT activity through direct enzyme interaction leading to demethylation and reactivation of genes previously silenced by methylation (see Figure 1 & Table 1) [77,93,94]. Early studies conducted by Fang et al. demonstrated that treatment of esophageal cancer cells with EGCG in fact lowered DNMT activity and caused a time- and dose-dependent reversal of hypermethylation in tumor suppressor genes including p16, RARβ, hMLH1 and MGMT [95]. A recent investigation involving A431 skin cancer cells revealed that EGCG treatment not only decreased global DNA methylation levels, but also decreased the levels of 5-methyl-cytosine, DNMT activity, mRNA and protein levels of DNMT1, DNMT3a and DNMT3b resulting in the re-expression of p16(INK4a) and p21/Cip1 mRNA and proteins [96]. In addition, in studies conducted by Li et al. it was found that EGCG is capable of reactivating estrogen receptor-α (ER-α) expression in ERα-negative MDA-MB-231 breast cancer cells [97]. This is of particular importance in breast cancer therapeutics where many treatment options utilize the ER pathway. Moreover, studies conducted by Berletch et al. indicated that EGCG treatment of MCF-7 breast cancer cells resulted in downregulation of the hTERT gene and a time dependent decrease in hTERT promoter methylation, which paradoxically leads to a decrease in telomerase activity in these cells [93]. In addition, EGCG has been demonstrated to demethylate the Wnt oncogene promoter in lung cells [98]. EGCG can also partially reverse the hypermethylation status of the RECK tumor suppressor gene in oral carcinoma cells, significantly enhancing the expression of RECK mRNA [99]. Moreover, treatment of LNCaP human prostate cancer cells with green tea polyphenol caused a time- and dose-dependent re-expression of GSTP1, whose overexpression has been associated with the development of several types of cancer [100]. In addition, Choi et al. have identified EGCG as a HAT inhibitor with global specificity for the majority of HAT enzymes [101]. Recently, EGCG has also been found to modulate miRNA expression in hepatocellular carcinoma cells (Figure 2 & Table 1) [102]. Furthermore, either EGCG or green tea polyphenols can inhibit carcinogenesis based on numerous in vivo studies; however, the effects on epigenetic mechanisms and the epigenome in vivo have not yet been clearly defined [103–105]. While considerable evidence has been presented showing the anticarcinogenic properties of green tea consumption, the EGCG compound is unstable under normal physiological conditions. To this end, synthetic analogs of EGCG have been studied in physiological conditions and show strong anticancer activity with more stability and efficacy [106]. Interestingly, studies conducted using EGCG and a prodrug of EGCG (pEGCG and EGCG octa-acetate) to enhance the bioavailability and stability of EGCG display inhibition of hTERT, the catalytic subunit of telomerase, through epigenetic mechanisms affecting the hTERT gene regulatory region in breast cancer cells [107,108]. Studies provide evidence that EGCG alone or combined with other epigenetic-modifying compounds such as HDAC inhibitors may be effective as cancer therapeutic agents and these lines of investigation are currently of considerable interest in the field of epi-genetics and in the development of an epigenetic diet for the purpose of cancer prevention. ResveratrolThe dietary polyphenol resveratrol is naturally found in several plants including peanuts, mulberries, cranberries and blueberries, but is most abundant in the skin of grapes [109]. Resveratrol is also consumed in the form of red wine. Antioxidant, anti-inflammatory and anti-cancer properties of resveratrol occur through various molecular and biochemical pathways [110,111]. For instance, resveratrol has an impact on signaling pathways that control cell division, cell growth, apoptosis, angiogenesis and tumor metastasis [112–114]. Antiproliferative properties of resveratrol have been reported in liver, skin, breast, prostate, lung and colon cancer cells [115–117]. It has also been demonstrated that colon carcinoma cells treated with resveratrol inhibits cell migration, adhesion and invasion [118]. The beneficial effects of resveratrol have also been demonstrated in vivo in that this bio-active dietary component has been reported to reduce adenocarcinoma cell metastases in BALB/c mice thereby increasing the percentage survival of the mice [119,120]. While resveratrol has potential as a dietary anticancer agent, it displays less DNMT inhibitory activity than some of its dietary counterparts including EGCG (Figure 1 & Table 1). However, resveratrol is capable of preventing the epigenetic silencing of the BRCA1 tumor suppressor protein [121] and Papoutsis et al. demonstrated that resveratrol-treated MCF-7 cells partially restored monomethylated-H3K9, DNMT1, and MBD2 at the BRCA1 promoter [121]. Inhibition of DNMT has been shown in nuclear extracts from MCF-7 breast cancer cells treated with resveratrol although resveratrol was unable to reverse the methylation of certain tumor suppressor genes [60]. In addition, resveratrol was unable to inhibit RARβ2 and MGMT promoter methylation in MCF-7 cells [122,123]. Importantly, resveratrol is associated with activating SIRT-1 and p300, which are known HDAC inhibitors [124]. As aforementioned, HDACs are responsible for removing acetyl groups from the lysine residues of histones. There are to date at least 18 HDAC isozymes that are divided into different classes. Several studies have reported a link between class I HDACs and the development of malignant tumors, while this link has been observed substantially less in class II HDACs [125]. Class III HDACs are homologous to the Sir2 protein in yeast and are collectively known as Sir proteins or sirtuins. Sirtuins have specific inhibitors and are not responsive to class I and II HDAC inhibitors [126]. The SIRT-1-encoded proteins are necessary for chemoprevention mediated by resveratrol [127]. It is believed that resveratrol activates SIRT-1 by mimicking physiological pathways that stimulate SIRT-1 [128,129]. The activation of SIRT-1 by resveratrol negatively regulates expression of the antiapoptotic protein, Survivin, by deacetylating H3K9 within the promoter of its gene [130,131]. In addition, studies conducted by Wang et al. found that SIRT-1 mediates BRCA1 signaling in human breast cancer cells by altering H3 acetylation [130]. Furthermore, treatment of prostate cancer cells with resveratrol demonstrates enhanced p53 acetylation and apoptosis by inhibition of the MTA–NuRD complex [132]. In terms of aging, resveratrol has also been reported to extend the lifespan and improve the health of mice on a high-calorie diet [133]. Sirturins typically exhibit their activity through deacetylation of nonhistone proteins but are also important in the maintenance of histone acetylation patterns [126,134]. This evidence suggests that sirturins can affect normal gene expression through chromatin regulation and may provide a link between epigenetic changes associated with aging and obesity as well as epigenetic modifications in tumors. CurcuminCurcumin, a diferuloylmethane, is a polyphenol that originates from the plant, Curcuma longa. Curcumin is the main component of the spice turmeric and is responsible for the yellow pigmentation of curry. This bioactive dietary component appears to have anti-inflammatory, antioxidant, antiangiogenic and anti-cancer properties and is used as a therapeutic agent in Indian and Chinese medicine [135,136]. Investigations indicate that curcumin inhibits DNMT activity (Figure 1 & Table 1) by covalently blocking the catalytic thiolate of C1226 of DNMT1 [137,138]. Moreover, there is evidence that curcumin may be an effective DNA hypomethylating agent that could facilitate the expression of inactive prometastatic and proto-oncogenes [16,77,137,139]. Curcumin also has epigenomic effects in that genomic DNA from leukemia cells show global hypomethylation after curcumin treatments [140]. In addition, studies conducted by Valinluck and Sowers indicated that curcumin induced anti-inflammatory effects. These effects stemmed from halogenated cytosine products that mimic 5-methylcytosine in DNA methylation. These data provide evidence of a link between inflammation and epigenetic alterations that are also seen in cancer [141]. Curcumin also functions as a histone modifying compound and as a HDAC and HAT inhibitor (Figure 3 & Table 1) [142]. While this inhibition is less than that of some other dietary epigenetic modifiers, Kang et al. found that the inhibition of curcumin-mediated HAT activity results in a decrease in global histone H3 and H4 acetylation in brain cells [142]. Furthermore, independent studies conducted by Cui and Pollack demonstrated that promoter hypoacetylation of several histones was curcumin-mediated and correlated to gene silencing [143,144]. In addition, numerous animal studies have built upon in vitro investigations and support the ability of curcumin to inhibit HATs and HDACs in several disease models including tumorigenesis [77,139,142,145–148]. While the inhibition of both HATs and HDACs may seem contradictory, recent investigations provide evidence that HAT inhibitors have a potential role in cancer therapies and that inhibition of both HATs and HDACs together may provide a potent strategy for cancer treatment [149]. Chemoprevention mediated by curcumin is mainly facilitated by the NF-κB and PI3K/AKT signaling pathway and typically induces cell cycle arrest and apoptosis [150]. Several groups have shown that curcumin is a potent inhibitor of p300/CBP activity in leukemia, hepatoma and cervical cancer cellular extracts [151,152]. There are also indications that curcumin prevents histone hyperacetylation induced by the MS-275 HDAC inhibitor in peripheral blood lymphocytes and cancer cells [151,153]. In addition, curcumin has been found to alter the miRNA expression profile in pancreatic cancer cell lines (Figure 2 & Table 1) [154,155]. Dietary modifiers of histones The data showing the strong inhibitory activity of curcumin in carcinogenesis suggests its therapeutic abilities in cancer or its use in chemoprevention. An issue with using curcumin as a bioactive agent is that its insolubility and instability in water leads to low bioavailability. However, the bioavailability of curcumin can be enhanced by utilizing properties of dietary factors such as rubusoside (found in Chinese blackberry extract) and molecular compounds such as phosphatidylcholine (found in soy and egg yolks) thereby increasing its potential in cancer chemoprevention or therapy [156,157]. Isoflavones (genistein)Isoflavones belong to the flavonoid group of compounds, the largest class of polyphenolic compounds [158]. Isoflavones are found in a number of plants including soybeans, fava beans and kudzu. Several isoflavones have been investigated and indications are that they have anti-angiogenic and anticancer properties. Genistein, a phytoestrogen primarily found in soybeans, is perhaps the most studied of these bioactive compounds. This estrogen-like compounds acts as a chemopreventative agent in several types of cancers [159]. In fact, moderate doses of genistein appear to induce inhibitory effects on cervical, prostate, colon and esophageal cancers [160–162]. Several mechanisms have been found to contribute to the anticarcinogenic properties of genistein including its ability to regulate gene transcription by affecting histone acetylation and/or DNA methylation [163]. Genistein treatment of esophageal squamous cell carcinoma partially reversed DNA hypermethylation and reactivated p16, RARβ and MGMT and a similar reversal was also seen in prostate cancer cells [162]. Further studies conducted in prostate cells indicate that genistein induces the expression of the tumor suppressor genes p16 and p21 by altering histone and promoter methylation [164,165]. Likewise, studies using breast cancer cells treated with a low (3.125 μM) concentration of genistein demethylated the promoter of the GSTP1 gene [166]. In addition, genistein-treated prostate and renal cells showed a reversal of hypermethylation of the BTG3 gene, a known tumor suppressor [167,168]. Moreover, genistein combined with DNA methylation inhibitors or other DNMTs can enhance the reactivation of genes silenced by methylation [163,169]. As evidence of this, Li et al. found that genistein inhibits DNMT1, 3a and 3b (Figure 1) and inhibits the expression of hTERT. Genistein also increases acetylation by enhancing HAT activity (Figure 3) [168]. Furthermore, investigations have demonstrated that genistein-mediated hypomethylation and hyperacetylation reactivate the expression of tumor suppressor genes in prostate cancer cells [164,165]. Genistein and other isoflavones have also been found to regulate miRNA expression in several cancer cell lines (Figure 2 & Table 1) [170,171]. Importantly, the effects of genistein have recently been tested in humans. For instance, in studies conducted by Qin et al., 34 healthy premenopausal women received either 40 mg or 140 mg of isoflavones, including genistein, daily through one menstrual cycle. Methylation assessment of five genes known to be methylated in breast cancer (p16, RASSIFA, RARβ2, ER and CCND2) was conducted on intraductal samples. The findings revealed hypermethylation (which typically leads to gene silencing) of cancer-related genes RARβ2 and CCND2 was increased after genistein treatment and correlated with serum genistein levels [172].
One of the main isothiocyanate compounds is SFN. SFN is an isothiocyanate found in cruciferous vegetables such as broccoli. Investigations into the effects of dietary SFN have shown its anticarcinogenic activity in several cancers [173,180–182]. SFN has many effects that include inducing apoptosis, affecting the cell cycle and acting as a HDAC inhibitor (Figure 3 & Table 1). SFN-initiated HDAC inhibition has been found to have epigenomic effects in that it can increase global and local histone acetylation of a number of genes and is thought to be involved in the regulation of cancer-related genes [183–185]. Studies conducted in colorectal and prostate cancer cells show inhibition of HDAC activity due to SFN treatments. In addition, studies conducted by Myzak et al. using human subjects demonstrated that a dose of 68 g of broccoli sprouts was effective in inhibiting HDAC activity in peripheral blood mononucleocytes [186]. In addition, studies conducted by Meeran et al. indicated that SFN can inhibit DNMTs in breast cancer cells and that SFN inhibits hTERT in a dose and time-dependent manner [59]. This finding is significant since hTERT is overexpressed in approximately 90% of cancers. жүктеу/скачать 1.88 Mb. Достарыңызбен бөлісу:
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