Next Article in Journal
Music Therapy and Other Music-Based Interventions in Pediatric Health Care: An Overview
Next Article in Special Issue
Effect of Sulforaphane and 5-Aza-2’-Deoxycytidine on Melanoma Cell Growth
Previous Article in Journal
Assessment of Artemisinin Contents in Selected Artemisia Species from Tajikistan (Central Asia)
Previous Article in Special Issue
The Multitarget Activity of Natural Extracts on Cancer: Synergy and Xenohormesis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Medicines
Volume 6
Issue 1
10.3390/medicines6010024
medicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Differential Methylation and Acetylation as the Epigenetic Basis of Resveratrol’s Anticancer Activity

by
Mohd Farhan
1,
Mohammad Fahad Ullah
2,
Mohd Faisal
3,
Ammad Ahmad Farooqi
4,
Uteuliyev Yerzhan Sabitaliyevich
5,
Bernhard Biersack
6 and
Aamir Ahmad
7,*
1
College of Basic Sciences, King Faisal University, Hofuf 400-Al Ahsa-31982, Saudi Arabia
2
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, P.O. Box 741, Tabuk 71491, Saudi Arabia
3
Department of Psychiatry, University Hospital Limerick, Limerick V94 T9PX, Ireland
4
Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan
5
Department of Postgraduate Education and Research, Kazakhstan Medical University KSPH, Almaty 050004, Kazakhstan
6
Organic Chemistry Laboratory, Department of Chemistry, University of Bayreuth, Universitaetsstrasse 30, 95447 Bayreuth, Germany
7
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
*
Author to whom correspondence should be addressed.
Medicines 2019, 6(1), 24; https://doi.org/10.3390/medicines6010024
Submission received: 11 January 2019 / Revised: 10 February 2019 / Accepted: 11 February 2019 / Published: 13 February 2019
(This article belongs to the Special Issue Natural Compounds as New Cancer Treatments)
Browse Figures
Versions Notes

Abstract

:
Numerous studies support the potent anticancer activity of resveratrol and its regulation of key oncogenic signaling pathways. Additionally, the activation of sirtuin 1, a deacetylase, by resveratrol has been known for many years, making resveratrol perhaps one of the earliest nutraceuticals with associated epigenetic activity. Such epigenetic regulation by resveratrol, and the mechanism thereof, has attracted much attention in the past decade. Focusing on methylation and acetylation, the two classical epigenetic regulations, we showcase the potential of resveratrol as an effective anticancer agent by virtue of its ability to induce differential epigenetic changes. We discuss the de-repression of tumor suppressors such as BRCA-1, nuclear factor erythroid 2-related factor 2 (NRF2) and Ras Associated Domain family-1α (RASSF-1α) by methylation, PAX1 by acetylation and the phosphatase and tensin homologue (PTEN) by both methylation and acetylation, in addition to the epigenetic regulation of oncogenic NF-κB and STAT3 signaling by resveratrol. Further, we evaluate the literature supporting the potentiation of HDAC inhibitors and the inhibition of DNMTs by resveratrol in different human cancers. This discussion underlines a robust epigenetic activity of resveratrol that warrants further evaluation, particularly in clinical settings.

1. Introduction

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) (Figure 1) is a naturally occurring polyphenol found in peanuts and the skin of grapes and berries. It is a phytoalexin produced in response to injury, ultraviolet radiation or a pathogen attack. The initial interest in resveratrol was because of its antioxidant properties [1], which led to the recognition of its chemopreventive ability [2]. Resveratrol was also found to generate reactive oxygen species, leading to effective anticancer activity through a prooxidant mechanism [3,4] which also happens to be a hallmark of several other polyphenols [5,6,7]. It is now believed that resveratrol exhibits both antioxidant and prooxidant properties [8,9,10], which depend largely on the tumor microenvironment and the presence of transition metal ions, particularly copper ions. Besides its anticancer properties, resveratrol has also been investigated to explain the ‘French paradox’ [11], a phenomenon of the relatively low incidence of coronary heart diseases in the French population despite a diet rich in saturated fats, perhaps due to the consumption of red wine with high resveratrol content.
The realization of the potent anticancer properties of resveratrol was followed by numerous investigations into the various signaling pathways that it affects, leading to the observed effects [12,13,14,15,16,17]. In recent years, the focus of cancer research has shifted to stem cells, epithelial-to-mesenchymal transition (EMT) and epigenetic regulation, even in the context of lead compounds such as resveratrol that have a natural origin. Accordingly, a number of studies have documented the ability of resveratrol to affect stem cell populations [18,19] and EMT [20,21]. This article focuses on epigenetic regulation by resveratrol, which is increasingly being proposed as contributing to its anticancer properties.

2. Epigenetic Regulation by Resveratrol

Even though ‘epigenetics’ was originally intended to define heritable changes in phenotypes that were independent of changes in the DNA sequence, the meaning of this word has now considerably broadened to describe the alterations in human chromatin that influence DNA-templated processes [22,23]. Epigenetic changes do not result in any changes in the DNA sequence, but can still have lasting effects on gene expression. Epigenetic changes involve at least four known modifications of DNA and sixteen classes of histone modifications [22,23,24].
A number of studies have recognized the effects of nutraceuticals, including polyphenol resveratrol, on the epigenetic machinery in humans [25,26,27,28,29,30,31,32,33,34,35]. Resveratrol can modulate epigenetic patterns by altering the levels of S-adenosylmethionine and S-adenosylhomocysteine or by directing the enzymes that catalyze DNA methylation and histone modifications [27]. It also activates the deacetylase sirtuin and regulates oncogenic and tumor suppressor micro-RNAs [36]. Methylation and acetylation are two classical epigenetic modifications, and these will be the subject of our discussion in this article as we showcase the epigenetic basis of the anticancer action of resveratrol.

3. Methylation

The DNA methylation of gene promoters has a profound effect on their eventual expression and function. Differential DNA methylation can lead to a disease condition in healthy phenotypes. This is particularly true for cancer wherein the differential DNA methylation of the promoters of oncogenes and tumor suppressor genes helps maintain a delicate balance. The increased (hyper) methylation of promoter CpG islands causes gene silencing, while the decreased (hypo) methylation of promoter CpG islands leads to the expression of the gene.

3.1. Breast Cancer

Breast cancer is a widely studied cancer when it comes to epigenetic regulation, particularly differential methylation, by resveratrol. Studies have been conducted to elucidate the genome-wide methylation patterns after resveratrol treatment, and there have also been efforts to understand the epigenetic basis of the de-repression of tumor suppressors by resveratrol. The subsection to follow will focus on this activity of resveratrol.

3.1.1. Genome-Wide Analyses

A study on the genome-wide methylation-modifying effects of resveratrol, which involved exposing MCF10CA1h and MCF10CA1a cells to resveratrol for 9 days followed by Illumina 450K array analysis, revealed a profound effect of resveratrol on genome-wide DNA methylation with approximately 75% differentially methylated genes being hypermethylated [37]. This study evaluated the epigenetic activity of not only resveratrol but also pterostilbene, an analog of resveratrol. While treatment with resveratrol was done at a dose of 15 μM, pterostilbene treatment was at a 7 μM dose. The compounds targeted genes that are over-expressed in tumors because of DNA hypomethylation. Since increased DNA methylation results in the silencing of genes, it makes sense that the resveratrol-induced hypermethylated genes have predominantly oncogenic functions [37], such as the Notch signaling pathway. However, in another study that also looked at genome-wide DNA methylation after resveratrol treatment (in this case, 24 h and 48 h treatment), only about 12.5% of CpG loci were found to be differentially methylated by resveratrol [38]. This study used MDA-MB-231 breast cancer cells and the concentration of resveratrol was 100 μM. Additionally, this study predominantly found DNA hypomethylation by resveratrol. It is possible that the differences in genome-wide DNA methylation (75% vs. 12.5%) in these two studies might be reflective of the different experimental setups, in particular, the time-durations of the resveratrol treatment as well as the doses used, with longer treatment leading to substantially more methylation.

3.1.2. Effects on Tumor Suppressors

Tumor suppressor genes are typically inactivated at the onset of tumorigenesis and, therefore, their reactivation by anticancer therapy is a mechanism through which tumor progression can be controlled. Several studies have documented the epigenetic reactivation of the tumor suppressor genes by resveratrol in breast cancer (Figure 2), as discussed below.
Phosphatase and tensin homologue (PTEN) is a well-characterized tumor suppressor in breast cancer [39]. In one of the earlier studies describing an effect of resveratrol on promoter DNA methylation, it was reported that resveratrol was highly efficient in reducing PTEN promoter DNA methylation in MCF7 breast cancer cells [40]. Since reduced DNA methylation leads to gene expression, this action of resveratrol induced the expression of PTEN which could explain its anticancer effects. Further, it was reported that the epigenetic effects were complex as not only PTEN was induced but the cell cycle regulator p21 was up-regulated as well, in addition to the down-regulation of DNMT (DNA methyltransferase). This is interesting because DNA methyltransferases increase methylation. Thus, it appears that resveratrol is able to reduce DNA methylation possibly through two different ways—by reducing methylation and by inducing de-methylation.
BRCA-1 (breast cancer type 1) is another tumor suppressor gene. Its expression is known to be regulated by epigenetic mechanisms. In a study that demonstrated the effects of resveratrol on BRCA-1 methylation [41], it was shown that exposure of breast cancer cells MCF7 to tumor promoter TCDD (2,3,7,8 tetrachlorodibenzo-p-dioxin) resulted in the hypermethylation of BRCA-1 promoter CpG island concomitant with an increased association of trimethylated histone H3K9 and DNMTs, namely DNMT1, DNMT3a and DNMT3b, with BRCA-1 promoter. Resveratrol, at physiologically relevant doses, was able to repress these TCDD effects. In a follow-up study, the research group evaluated the effects of TCDD alone, and in combination with resveratrol, on pregnant Sprague–Dawley rats [42]. It was found that, similar to in vitro observations in MCF7 cells, gestational exposure to TCDD led to the reduced DNA CpG island methylation of BRCA-1 promoter in the mammary tissues of the offspring, which was preceded by the occupation of BRCA-1 promoter by DNMT-1. Also, confirming a possible therapeutic role, resveratrol was found to partially attenuate TCDD effects [42].
Nuclear factor erythroid 2-related factor 2 (NRF2) is also a tumor suppressor that is epigenetically regulated by resveratrol. In a study that looked at the effects of resveratrol on E2 (17β-estradiol)-induced carcinogenesis [43], resveratrol alone up-regulated NRF2 in mammary tissues of rats, and attenuated the repressive effects of E2 on NRF2. E2 suppressed NRF2 through DNA methylation, an activity that was inhibited by resveratrol, thus providing further evidence in support of its regulation of promoter DNA methylation in breast cancer.

3.1.3. DNMTs as Mediators of Resveratrol Effects in Breast Cancer

There is much evidence supporting an inhibitory effect of resveratrol against DNMTs [40,41,44,45,46]. However, most of the evidence comes from in vitro studies. To validate these findings, a pilot study was conducted that enrolled 39 women with increased breast cancer risk [47]. The subjects were divided into three groups—placebo and those receiving 5 or 50 mg resveratrol. Resveratrol was administered twice daily for twelve weeks and the focus was on the DNA methylation of four cancer-related genes—p16, Ras Associated Domain family-1α (RASSF-1α), Adenomatous Polyposis Coli (APC) and Cyclin D2 (CCND2). An inverse relationship between serum resveratrol levels and RASSF-1α methylation was observed, i.e., when resveratrol levels increased, the methylation of RASSF-1α decreased, thus leading to the expression of this tumor suppressor gene. In another study by this group [48], an in vivo effect of resveratrol on DNMT expression was examined in normal vs. tumor tissues. The model evaluated was ACI rats, an inbred line derived from the August and Copenhagen strains. An interesting observation was that resveratrol affected DNMT3b, but not DNMT1. Two different doses of resveratrol were tested and while DNMT3b differed in normal vs. tumor tissues of rats treated with low resveratrol, a high resveratrol dose resulted in decreased DNMT3b in tumor tissues with increased DNMT3b in the normal tissues [48]. This observation is a little different from the one performed in vitro in immortalized breast cancer epithelial cells, MCF10A [49], where resveratrol, at a non-cytotoxic dose, only induced subtle changes in the DNA methylation of eight pre-determined genes. However, the involvement of DNMT3b in resveratrol activity was also identified in a genome-wide DNA methylation study in breast cancer cells [37].
Further confirming the importance of targeting DNMTs in breast cancer patients, the elevated expression of DNMT transcripts was reported in a study that evaluated breast cancer tissues from 40 breast cancer patients and compared those with tissues from 10 paired normal breast tissues [50]. This study further confirmed the down-regulation of DNMT transcripts in vitro in breast cancer cells.

3.2. Glioma

Glioblastoma multiforme was the other malignancy where evidence of the effect of resveratrol on methylation was initially presented. It was shown that resveratrol could sensitize resistant glioblastoma T98G cells to temozolomide, inhibiting temozolomide IC-50 with increased apoptosis [51]. Interestingly, temozolomide-resistant cells have increased MGMT (O(6)-methylguanine-DNA-methyltransferase) activity and the protein expression of MGMT is an important determinant of temozolomide-resistance [51]. These results are suggestive of yet another DNA methylation-suppressing activity of resveratrol. In a recent report, inhibition of Wnt signaling has been identified as the mechanism by which resveratrol induces cell death in T98G cells [52]. Epigenetic regulation has been identified as one of the bases of perturbed Wnt signaling [53] and it is plausible that Wnt signaling might be another piece in the puzzle.

3.3. Lung Cancer

Lung cancer, the majority of which is non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths in the United States, as well as worldwide. A number of studies have described the inhibitory effects of resveratrol against various lung cancer models [54,55,56], albeit, a majority of the studies have focused on NSCLC with little information on the other lung cancer types. In recent years, efforts have been made towards the personalized management of lung cancer [57], with a focus on epigenetics in such personalized therapy [58]. Further, it has recently been demonstrated that resveratrol can epigenetically regulate the expression of zinc finger protein36 (ZFP36) through differential DNA methylation [59]. Specifically, resveratrol reduced the methylation of ZFP36, resulting in its up-regulation in A549 NSCLC cells. A role of ZFP36 in human malignancies is increasingly being realized, making it an attractive target for therapy [60]. Thus, its epigenetic targeting by resveratrol further underlines the anticancer potential of resveratrol, particularly in lung cancer.

4. Acetylation

Even before the realization of the methylation potential of resveratrol, it has been known to modulate acetylation within the cellular microenvironment. A quarter century back, resveratrol was reported to be an activator of sirtuin-1 (SIRT1), the NAD-dependent deacetylase, marking its influence on acetylation, and thereby epigenetic regulation [61]. While the activity of resveratrol against Class III HDACs sirtuins is well characterized, it has been suggested that perhaps resveratrol possesses a pan-HDAC inhibitory property and can inhibit HDACs representing class I, class II as well as class IV [62]. Recently, resveratrol has been identified as an inhibitor of bromodomains [63] and the bromodomain and extraterminal (BET) family [64]. Bromodomains affect epigenetic machinery by recognizing lysine acetylation on histones, thereby functioning as epigenetic readers. The interactions of resveratrol with bromodomains open yet another mechanism of epigenetic regulation by resveratrol which is not yet fully explored. The next few subsections discuss the reported effects of resveratrol on the acetylation of different genes in various human cancers.

4.1. Breast Cancer

Acetylation and its impact on breast cancer progression is well appreciated. It is because of this knowledge that HDAC inhibitors still remain an attractive therapeutic strategy against breast cancers [65,66,67]. It is not only the HDAC inhibitors but also the inhibitors of HATs (histone acetyltransferases) that are being evaluated [68], which provides a good example of how dynamic the process of acetylation and deacetylation is, and how an imbalance can lead to tumor onset and progression. In a study [69] that is indicative of an intricate connection between methylation and acetylation, the two classical epigenetic modifications, it was reported that lysine acetylation within the signal transducer and activator of transcription 3 (STAT3) can impact the interaction of DNMT1 with STAT3 and is accompanied by the demethylation and, thereby, the re-expression of tumor suppressor genes. This study used resveratrol as an acetylation inhibitor and the observations in triple negative breast cancer (TNBC) were further confirmed in melanoma. TNBCs are characterized by the absence of the estrogen receptor (ER) and progesterone receptor (PR), as well as human epidermal growth factor receptor 2 (HER2), and it has been reported that the absence of the ERα gene in tumor cells is often a result of methylation [70]. With the observation that STAT3 is acetylated and, therefore, highly expressed in TNBCs, it was evaluated whether inhibiting STAT3 acetylation could reactivate ERα [69]. The TNBC cell line MDA-MB-468 was used as the model and it was observed that treatment with resveratrol significantly reduced STAT3 acetylation as well as ERα gene promoter DNA methylation (Figure 3). This resulted in the increased expression of ERα and the sensitization of otherwise resistant cells to the ER-targeted therapy, tamoxifen. Further, growth of in vivo tumors in mice was not significantly reduced by tamoxifen alone, as expected, but by the combinational treatment comprising resveratrol and tamoxifen, thus validating the in vitro findings [69]. As further evidence of the effect of resveratrol on acetylation in breast cancer, in MCF-7 breast cancer cells, resveratrol has been shown to induce H3 acetylation [71]. Thus, there seems to be evidence suggesting a modulatory effect of resveratrol on protein as well as histone acetylation.

4.2. Cervical Cancer

In cervical cancer models, paired box gene1 (PAX1) is a tumor suppressor whose expression is repressed during tumorigenesis by DNA hypermethylation. In a study that evaluated the effect of nutraceuticals, including resveratrol, on the inhibition of cervical cancer through the reactivation of PAX1, it was reported that resveratrol was capable of reactivating PAX1 expression in Caski cells [72]. However, surprisingly, the reactivation of PAX1 was not found to be due to the effect of resveratrol on the DNA methylation of PAX1 promoter. Rather, it possibly involved the acetylation modulating ability of resveratrol through its regulation of HDAC activity. Similar to an effect of resveratrol on histone H3 acetylation in breast cancer cells above, resveratrol has been reported to induce H3 acetylation in HeLa cervical cancer cells as well [71]. Such an effect of resveratrol on H3 acetylation assumes significance given the proposed role of histone H3 acetylation as a prognostic marker for cervical cancer patients [73].

4.3. Colon Cancer

NF-κB signaling is known to be important to the progression of colon cancer [74], especially in resistance to cisplatin [75]. An increase in the protein acetylation of the NF-κB p65 subunit leads to the activation of the NF-κB pathway and its nuclear accumulation. Therefore, the inhibition of the acetylation of p65 can potentially be an effective strategy to check the growth of colon cancer as well as to overcome resistance to cisplatin. In an in vitro study performed in HK2 cells, resveratrol was found to decrease the protein acetylation of the p65 subunit, thus reversing the cell viability-inducing activity of cisplatin [76]. Such down-regulation of NF-κB protein acetylation by resveratrol in colorectal cells was confirmed in another study [77] and this resulted in reduced tumor invasion and metastasis because of the down regulation of NF-κB-regulated factors, such as MMP-9 and CXCR4.

4.4. Leukemia and Lymphoma

In leukemia, resveratrol can potentiate the activity of HDAC inhibitors [78], while in a Hodgkin lymphoma represented by L-428 cells, resveratrol can effectively induce apoptosis as well as cell cycle arrest [79]. As the mechanism, it was observed that resveratrol induced the tumor suppressor p53 through an increase in the p53 K373-acetylation (Table 1). Additionally, resveratrol treatment was found to induce the lysine acetylation of FOXO3a [79]. In leukemia U937 cells, resveratrol potentiates reactive oxygen species production by retinoic acid, particularly the production of superoxide anions, primarily through the up-regulation of the gp91-phox gene that is part of the membrane-bound cytochrome b558 [80]. As a mechanism, it was elucidated that resveratrol promoted acetylation within the promoter region of the gp91-phox gene, particularly the Lys-9 residues and Lys-14 residues of histone H3 within the chromatin surrounding the gene promoter.

4.5. Prostate Cancer

In prostate cancer, metastasis-associated protein 1 (MTA1) is oncogenic with its expression correlating with tumor progression. It is itself involved in the transcriptional repression of target genes through the post-translational modifications of histones as well as non-histones by virtue of it being a part of the nucleosome remodeling deacetylation corepressor complex, the ‘NuRD complex’. Resveratrol was shown to down-regulate MTA1, leading to acetylation and the activation of the tumor suppressor p53 through the destabilization of the corepressor complex [81]. The NuRD complex plays a role in maintaining chromatin conformation, which it achieves through the deacetylation of histone proteins [82]. HDAC1 and HDA2 are components of the NuRD complex, with the MTA1-HDAC1 subunit responsible for the deacetylation of histones by NuRD. With a direct regulation of MTA1, and the observation that HDAC1 was decreased in resveratrol-treated MTA1 immunoprecipitates, it is evident that resveratrol has a profound effect on histone acetylation. Further, the effects of resveratrol were similar to those of the HDAC inhibitor SAHA, thus underlying the acetylation-affecting epigenetic activity of resveratrol. The results were further confirmed in vivo in a follow-up study [83], and it was shown that the MTA1-mediated tumor progression was, in part, due to PTEN inactivation and that resveratrol could acetylate and reactivate PTEN [84] (Table 1).
Signaling through the androgen receptor (AR) is important in prostate cancer, even in the advanced castrate-resistant prostate cancers. In a study that specifically looked at the regulation of AR signaling by resveratrol, it was observed that treatment with 10 μM resveratrol for just 3 h inhibited the acetylation of AR and affected the binding of AR to the enhancer region of prostate-specific antigen (PSA) [85]. At a slightly longer treatment of 24 h, resveratrol inhibited the nuclear accumulation of AR as well. Given the important role that AR plays in prostate cancer, such epigenetic regulation of its activity and the effect on down-stream signaling by resveratrol is an encouraging finding that gives hope for its possible use as a therapy against prostate cancer.

5. Conclusions and Perspectives

While various cellular signaling pathways and genes (oncogenes as well as tumor suppressor genes) are still being evaluated as therapeutic targets of anticancer agents such as resveratrol, in recent years, attention has also turned to epigenetic regulation. In fact, epigenetic regulation of classical signaling pathways is increasingly being realized. For example, two of the very well characterized signaling pathways, NF-κB and STAT3, are epigenetically regulated by resveratrol [69,76,77,86]. This represents a fundamental evolution in our understanding with regards to the intricate regulation of oncogenic pathways. Our discussion on the topic, as presented in this article, detailed many studies that provided evidence supporting the epigenetic activity of resveratrol. However, resveratrol does not regulate gene expression only through epigenetic mechanisms. For example, in a study in acute lymphoblastic leukemia [87] that looked at the possible effect of resveratrol on the methylation of MDR1 (multidrug resistance gene 1), no evidence of the differential DNA methylation of MDR1 promoter by resveratrol was found. While resveratrol had a visible suppressive effect on MDR1, there did not seem to be any epigenetic perspective. This is a perfect reminder that not all regulation of gene expression and function by resveratrol has an epigenetic basis. Additionally, regulation through microRNAs (miRNAs) is within the realm of epigenetic regulation, but we decided to cover just the classical epigenetic mechanisms with regards to methylation and acetylation so as to keep the discussion more focused. Finally, the bioavailability of resveratrol still remains a concern, but that should not deter us from fully elucidating its mechanism of action and its potential as a viable anticancer lead. Several groups are working hard on improving the bioavailability through novel approaches and once they achieve success, resveratrol should be ready for further evaluations in clinical settings as an anticancer agent with multifaceted epigenetic activity.

Funding

Mohd Farhan is thankful to the Deanship of Scientific Research, King Faisal University, for a research grant through the Nasher track (186105).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Miller, N.J.; Rice-Evans, C.A. Antioxidant activity of resveratrol in red wine. Clin. Chem. 1995, 41, 1789. [Google Scholar] [PubMed]
  2. Jang, M.; Cai, L.; Udeani, G.O.; Slowing, K.V.; Thomas, C.F.; Beecher, C.W.; Fong, H.H.; Farnsworth, N.R.; Kinghorn, A.D.; Mehta, R.G.; et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997, 275, 218–220. [Google Scholar] [CrossRef] [PubMed]
  3. Ahmad, A.; Farhan Asad, S.; Singh, S.; Hadi, S.M. DNA breakage by resveratrol and cu(ii): Reaction mechanism and bacteriophage inactivation. Cancer Lett. 2000, 154, 29–37. [Google Scholar] [CrossRef]
  4. Ahmad, A.; Syed, F.A.; Singh, S.; Hadi, S.M. Prooxidant activity of resveratrol in the presence of copper ions: Mutagenicity in plasmid DNA. Toxicol. Lett. 2005, 159, 1–12. [Google Scholar] [CrossRef]
  5. Khan, H.Y.; Zubair, H.; Faisal, M.; Ullah, M.F.; Farhan, M.; Sarkar, F.H.; Ahmad, A.; Hadi, S.M. Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: A mechanism for cancer chemopreventive action. Mol. Nutr. Food Res. 2014, 58, 437–446. [Google Scholar] [CrossRef] [PubMed]
  6. Khan, H.Y.; Zubair, H.; Ullah, M.F.; Ahmad, A.; Hadi, S.M. A prooxidant mechanism for the anticancer and chemopreventive properties of plant polyphenols. Curr. Drug Targets 2012, 13, 1738–1749. [Google Scholar] [CrossRef] [PubMed]
  7. Farhan, M.; Oves, M.; Chibber, S.; Hadi, S.M.; Ahmad, A. Mobilization of nuclear copper by green tea polyphenol epicatechin-3-gallate and subsequent prooxidant breakage of cellular DNA: Implications for cancer chemotherapy. Int. J. Mol. Sci. 2016, 18, 34. [Google Scholar] [CrossRef] [PubMed]
  8. de la Lastra, C.A.; Villegas, I. Resveratrol as an antioxidant and pro-oxidant agent: Mechanisms and clinical implications. Biochem. Soc. Trans. 2007, 35, 1156–1160. [Google Scholar] [CrossRef] [PubMed]
  9. Casey, S.C.; Amedei, A.; Aquilano, K.; Azmi, A.S.; Benencia, F.; Bhakta, D.; Bilsland, A.E.; Boosani, C.S.; Chen, S.; Ciriolo, M.R.; et al. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin. Cancer Biol. 2015, 35, S199–S223. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Chen, C.Y.; Kao, C.L.; Liu, C.M. The cancer prevention, anti-inflammatory and anti-oxidation of bioactive phytochemicals targeting the tlr4 signaling pathway. Int. J. Mol. Sci. 2018, 19, 2729. [Google Scholar] [CrossRef]
  11. Kopp, P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the ‘french paradox’? Eur. J. Endocrinol. 1998, 138, 619–620. [Google Scholar] [CrossRef] [PubMed]
  12. Shukla, Y.; Singh, R. Resveratrol and cellular mechanisms of cancer prevention. Ann. N. Y. Acad. Sci. 2011, 1215, 1–8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Yang, X.; Li, X.; Ren, J. From french paradox to cancer treatment: Anti-cancer activities and mechanisms of resveratrol. Anti-Cancer Agents Med. Chem. 2014, 14, 806–825. [Google Scholar] [CrossRef]
  14. McCalley, A.E.; Kaja, S.; Payne, A.J.; Koulen, P. Resveratrol and calcium signaling: Molecular mechanisms and clinical relevance. Molecules 2014, 19, 7327–7340. [Google Scholar] [CrossRef] [PubMed]
  15. Farooqi, A.A.; Wu, S.J.; Chang, Y.T.; Tang, J.Y.; Li, K.T.; Ismail, M.; Liaw, C.C.; Li, R.N.; Chang, H.W. Activation and inhibition of atm by phytochemicals: Awakening and sleeping the guardian angel naturally. Arch. Immunol. Ther. Exp. 2015, 63, 357–366. [Google Scholar] [CrossRef] [PubMed]
  16. de Oliveira, M.R.; Nabavi, S.F.; Manayi, A.; Daglia, M.; Hajheydari, Z.; Nabavi, S.M. Resveratrol and the mitochondria: From triggering the intrinsic apoptotic pathway to inducing mitochondrial biogenesis, a mechanistic view. Biochimi. Biophys. Acta 2016, 1860, 727–745. [Google Scholar] [CrossRef] [PubMed]
  17. Zhang, L.; Wen, X.; Li, M.; Li, S.; Zhao, H. Targeting cancer stem cells and signaling pathways by resveratrol and pterostilbene. BioFactors 2018, 44, 61–68. [Google Scholar] [CrossRef]
  18. Sarkar, F.H.; Li, Y.; Wang, Z.; Kong, D. The role of nutraceuticals in the regulation of wnt and hedgehog signaling in cancer. Cancer Metast. Rev. 2010, 29, 383–394. [Google Scholar] [CrossRef]
  19. McCubrey, J.A.; Lertpiriyapong, K.; Steelman, L.S.; Abrams, S.L.; Yang, L.V.; Murata, R.M.; Rosalen, P.L.; Scalisi, A.; Neri, L.M.; Cocco, L.; et al. Effects of resveratrol, curcumin, berberine and other nutraceuticals on aging, cancer development, cancer stem cells and micrornas. Aging 2017, 9, 1477–1536. [Google Scholar] [CrossRef]
  20. Karimi Dermani, F.; Saidijam, M.; Amini, R.; Mahdavinezhad, A.; Heydari, K.; Najafi, R. Resveratrol inhibits proliferation, invasion, and epithelial-mesenchymal transition by increasing mir-200c expression in hct-116 colorectal cancer cells. J. Cell. Biochem. 2017, 118, 1547–1555. [Google Scholar] [CrossRef]
  21. Xu, J.; Liu, D.; Niu, H.; Zhu, G.; Xu, Y.; Ye, D.; Li, J.; Zhang, Q. Resveratrol reverses doxorubicin resistance by inhibiting epithelial-mesenchymal transition (emt) through modulating pten/akt signaling pathway in gastric cancer. J. Exp. Clin. Cancer Res. 2017, 36, 19. [Google Scholar] [CrossRef] [PubMed]
  22. Dawson, M.A.; Kouzarides, T. Cancer epigenetics: From mechanism to therapy. Cell 2012, 150, 12–27. [Google Scholar] [CrossRef] [PubMed]
  23. Ahmad, A.; Li, Y.; Bao, B.; Kong, D.; Sarkar, F.H. Epigenetic regulation of mirna-cancer stem cells nexus by nutraceuticals. Mol. Nutr. Food Res. 2014, 58, 79–86. [Google Scholar] [CrossRef] [PubMed]
  24. Baylin, S.B.; Jones, P.A. A decade of exploring the cancer epigenome—biological and translational implications. Nat. Rev. Cancer 2011, 11, 726–734. [Google Scholar] [CrossRef] [PubMed]
  25. Vanden Berghe, W. Epigenetic impact of dietary polyphenols in cancer chemoprevention: Lifelong remodeling of our epigenomes. Pharmacol. Res. 2012, 65, 565–576. [Google Scholar] [CrossRef] [PubMed]
  26. Hardy, T.M.; Tollefsbol, T.O. Epigenetic diet: Impact on the epigenome and cancer. Epigenomics 2011, 3, 503–518. [Google Scholar] [CrossRef] [PubMed]
  27. Park, L.K.; Friso, S.; Choi, S.W. Nutritional influences on epigenetics and age-related disease. Proc. Nutr. Soc. 2012, 71, 75–83. [Google Scholar] [CrossRef] [PubMed]
  28. Gerhauser, C. Cancer chemoprevention and nutriepigenetics: State of the art and future challenges. Top. Curr. Chem. 2013, 329, 73–132. [Google Scholar] [PubMed]
  29. Wang, Y.; Li, Y.; Liu, X.; Cho, W.C. Genetic and epigenetic studies for determining molecular targets of natural product anticancer agents. Curr. Cancer Drug Targets 2013, 13, 506–518. [Google Scholar] [CrossRef] [PubMed]
  30. Vahid, F.; Zand, H.; Nosrat-Mirshekarlou, E.; Najafi, R.; Hekmatdoost, A. The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases: A review. Gene 2015, 562, 8–15. [Google Scholar] [CrossRef] [PubMed]
  31. Gao, Y.; Tollefsbol, T.O. Impact of epigenetic dietary components on cancer through histone modifications. Curr. Med. Chem. 2015, 22, 2051–2064. [Google Scholar] [CrossRef] [PubMed]
  32. Kala, R.; Tollefsbol, T.O. A novel combinatorial epigenetic therapy using resveratrol and pterostilbene for restoring estrogen receptor-alpha (eralpha) expression in eralpha-negative breast cancer cells. PLoS ONE 2016, 11, e0155057. [Google Scholar] [CrossRef] [PubMed]
  33. Fernandes, G.F.S.; Silva, G.D.B.; Pavan, A.R.; Chiba, D.E.; Chin, C.M.; Dos Santos, J.L. Epigenetic regulatory mechanisms induced by resveratrol. Nutrients 2017, 9, 1201. [Google Scholar] [CrossRef] [PubMed]
  34. Lee, P.S.; Chiou, Y.S.; Ho, C.T.; Pan, M.H. Chemoprevention by resveratrol and pterostilbene: Targeting on epigenetic regulation. BioFactors 2018, 44, 26–35. [Google Scholar] [CrossRef] [PubMed]
  35. Singh, A.K.; Bishayee, A.; Pandey, A.K. Targeting histone deacetylases with natural and synthetic agents: An emerging anticancer strategy. Nutrients 2018, 10, 731. [Google Scholar] [CrossRef]
  36. Stefanska, B.; Karlic, H.; Varga, F.; Fabianowska-Majewska, K.; Haslberger, A. Epigenetic mechanisms in anti-cancer actions of bioactive food components--the implications in cancer prevention. Br. J. Pharmacol. 2012, 167, 279–297. [Google Scholar]
  37. Lubecka, K.; Kurzava, L.; Flower, K.; Buvala, H.; Zhang, H.; Teegarden, D.; Camarillo, I.; Suderman, M.; Kuang, S.; Andrisani, O.; et al. Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic notch signaling through epigenetic regulation of maml2 transcriptional activity. Carcinogenesis 2016, 37, 656–668. [Google Scholar] [CrossRef]
  38. Medina-Aguilar, R.; Perez-Plasencia, C.; Marchat, L.A.; Gariglio, P.; Garcia Mena, J.; Rodriguez Cuevas, S.; Ruiz-Garcia, E.; Astudillo-de la Vega, H.; Hernandez Juarez, J.; Flores-Perez, A.; et al. Methylation landscape of human breast cancer cells in response to dietary compound resveratrol. PLoS ONE 2016, 11, e0157866. [Google Scholar] [CrossRef]
  39. Ramaiah, M.J.; Vaishnave, S. Bmi1 and pten are key determinants of breast cancer therapy: A plausible therapeutic target in breast cancer. Gene 2018, 678, 302–311. [Google Scholar]
  40. Stefanska, B.; Salame, P.; Bednarek, A.; Fabianowska-Majewska, K. Comparative effects of retinoic acid, vitamin d and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br. J. Nutr. 2012, 107, 781–790. [Google Scholar] [CrossRef]
  41. Papoutsis, A.J.; Borg, J.L.; Selmin, O.I.; Romagnolo, D.F. Brca-1 promoter hypermethylation and silencing induced by the aromatic hydrocarbon receptor-ligand tcdd are prevented by resveratrol in mcf-7 cells. J. Nutr. Biochem. 2012, 23, 1324–1332. [Google Scholar] [CrossRef] [PubMed]
  42. Papoutsis, A.J.; Selmin, O.I.; Borg, J.L.; Romagnolo, D.F. Gestational exposure to the ahr agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin induces brca-1 promoter hypermethylation and reduces brca-1 expression in mammary tissue of rat offspring: Preventive effects of resveratrol. Mol. Carcinog. 2015, 54, 261–269. [Google Scholar] [CrossRef] [PubMed]
  43. Singh, B.; Shoulson, R.; Chatterjee, A.; Ronghe, A.; Bhat, N.K.; Dim, D.C.; Bhat, H.K. Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of nrf2-mediated protective pathways. Carcinogenesis 2014, 35, 1872–1880. [Google Scholar] [CrossRef] [PubMed]
  44. Singh, V.; Sharma, P.; Capalash, N. DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer. Curr. Cancer Drug Targets 2013, 13, 379–399. [Google Scholar] [CrossRef] [PubMed]
  45. Kala, R.; Shah, H.N.; Martin, S.L.; Tollefsbol, T.O. Epigenetic-based combinatorial resveratrol and pterostilbene alters DNA damage response by affecting sirt1 and dnmt enzyme expression, including sirt1-dependent gamma-h2ax and telomerase regulation in triple-negative breast cancer. BMC Cancer 2015, 15, 672. [Google Scholar] [CrossRef] [PubMed]
  46. Gao, Y.; Tollefsbol, T.O. Combinational proanthocyanidins and resveratrol synergistically inhibit human breast cancer cells and impact epigenetic(-)mediating machinery. Int. J. Mol. Sci. 2018, 19, 2204. [Google Scholar] [CrossRef] [PubMed]
  47. Zhu, W.; Qin, W.; Zhang, K.; Rottinghaus, G.E.; Chen, Y.C.; Kliethermes, B.; Sauter, E.R. Trans-resveratrol alters mammary promoter hypermethylation in women at increased risk for breast cancer. Nutr. Cancer 2012, 64, 393–400. [Google Scholar] [CrossRef]
  48. Qin, W.; Zhang, K.; Clarke, K.; Weiland, T.; Sauter, E.R. Methylation and mirna effects of resveratrol on mammary tumors vs. Normal tissue. Nutr. Cancer 2014, 66, 270–277. [Google Scholar] [CrossRef]
  49. Beetch, M.; Lubecka, K.; Kristofzski, H.; Suderman, M.; Stefanska, B. Subtle alterations in DNA methylation patterns in normal cells in response to dietary stilbenoids. Mol. Nutr. Food Res. 2018, 2018, e1800193. [Google Scholar] [CrossRef]
  50. Mirza, S.; Sharma, G.; Parshad, R.; Gupta, S.D.; Pandya, P.; Ralhan, R. Expression of DNA methyltransferases in breast cancer patients and to analyze the effect of natural compounds on DNA methyltransferases and associated proteins. J. Breast Cancer 2013, 16, 23–31. [Google Scholar] [CrossRef]
  51. Huang, H.; Lin, H.; Zhang, X.; Li, J. Resveratrol reverses temozolomide resistance by downregulation of mgmt in t98g glioblastoma cells by the nf-kappab-dependent pathway. Oncol. Rep. 2012, 27, 2050–2056. [Google Scholar] [PubMed]
  52. Yang, H.C.; Wang, J.Y.; Bu, X.Y.; Yang, B.; Wang, B.Q.; Hu, S.; Yan, Z.Y.; Gao, Y.S.; Han, S.Y.; Qu, M.Q. Resveratrol restores sensitivity of glioma cells to temozolamide through inhibiting the activation of wnt signaling pathway. J. Cell. Physiol. 2018, 2018. [Google Scholar] [CrossRef]
  53. Koval, A.; Katanaev, V.L. Dramatic dysbalancing of the wnt pathway in breast cancers. Sci. Rep. 2018, 8, 7329. [Google Scholar] [CrossRef] [PubMed]
  54. Zhu, Y.; He, W.; Gao, X.; Li, B.; Mei, C.; Xu, R.; Chen, H. Resveratrol overcomes gefitinib resistance by increasing the intracellular gefitinib concentration and triggering apoptosis, autophagy and senescence in pc9/g nsclc cells. Sci. Rep 2015, 5, 17730. [Google Scholar] [CrossRef] [PubMed]
  55. Li, W.; Ma, X.; Li, N.; Liu, H.; Dong, Q.; Zhang, J.; Yang, C.; Liu, Y.; Liang, Q.; Zhang, S.; et al. Resveratrol inhibits hexokinases ii mediated glycolysis in non-small cell lung cancer via targeting akt signaling pathway. Exp. Cell Res. 2016, 349, 320–327. [Google Scholar] [CrossRef]
  56. Wang, J.; Li, J.; Cao, N.; Li, Z.; Han, J.; Li, L. Resveratrol, an activator of sirt1, induces protective autophagy in non-small-cell lung cancer via inhibiting akt/mtor and activating p38-mapk. OncoTargets Ther. 2018, 11, 7777–7786. [Google Scholar] [CrossRef] [PubMed]
  57. Ahmad, A.; Gadgeel, S.M. Lung cancer and personalized medicine: Novel therapies and clinical management. Preface. Adv. Exp. Med. Biol. 2016, 890, v–vi. [Google Scholar]
  58. Ahmad, A. Epigenetics in personalized management of lung cancer. Adv Exp Med Biol 2016, 890, 111–122. [Google Scholar]
  59. Fudhaili, A.; Yoon, N.A.; Kang, S.; Ryu, J.; Jeong, J.Y.; Lee, D.H.; Kang, S.S. Resveratrol epigenetically regulates the expression of zinc finger protein 36 in nonsmall cell lung cancer cell lines. Oncol. Rep. 2019, 41, 1377–1386. [Google Scholar]
  60. Gupta, G.; Bebawy, M.; Pinto, T.J.A.; Chellappan, D.K.; Mishra, A.; Dua, K. Role of the tristetraprolin (zinc finger protein 36 homolog) gene in cancer. Crit. Rev. Eukaryot. Gene. Expr. 2018, 28, 217–221. [Google Scholar] [CrossRef]
  61. Howitz, K.T.; Bitterman, K.J.; Cohen, H.Y.; Lamming, D.W.; Lavu, S.; Wood, J.G.; Zipkin, R.E.; Chung, P.; Kisielewski, A.; Zhang, L.L.; et al. Small molecule activators of sirtuins extend saccharomyces cerevisiae lifespan. Nature 2003, 425, 191–196. [Google Scholar] [CrossRef] [PubMed]
  62. Venturelli, S.; Berger, A.; Bocker, A.; Busch, C.; Weiland, T.; Noor, S.; Leischner, C.; Schleicher, S.; Mayer, M.; Weiss, T.S.; et al. Resveratrol as a pan-hdac inhibitor alters the acetylation status of histone [corrected] proteins in human-derived hepatoblastoma cells. PLoS ONE 2013, 8, e73097. [Google Scholar]
  63. Dutra, L.A.; Heidenreich, D.; Silva, G.; Man Chin, C.; Knapp, S.; Santos, J.L.D. Dietary compound resveratrol is a pan-bet bromodomain inhibitor. Nutrients 2017, 9, 1172. [Google Scholar] [CrossRef] [PubMed]
  64. Sahni, J.M.; Keri, R.A. Targeting bromodomain and extraterminal proteins in breast cancer. Pharmacol. Res. 2018, 129, 156–176. [Google Scholar] [CrossRef] [PubMed]
  65. Garmpis, N.; Damaskos, C.; Garmpi, A.; Kalampokas, E.; Kalampokas, T.; Spartalis, E.; Daskalopoulou, A.; Valsami, S.; Kontos, M.; Nonni, A.; et al. Histone deacetylases as new therapeutic targets in triple-negative breast cancer: Progress and promises. Cancer Genom. Proteom. 2017, 14, 299–313. [Google Scholar]
  66. Damaskos, C.; Garmpis, N.; Valsami, S.; Kontos, M.; Spartalis, E.; Kalampokas, T.; Kalampokas, E.; Athanasiou, A.; Moris, D.; Daskalopoulou, A.; et al. Histone deacetylase inhibitors: An attractive therapeutic strategy against breast cancer. Anticancer Res. 2017, 37, 35–46. [Google Scholar] [CrossRef]
  67. Zucchetti, B.; Shimada, A.K.; Katz, A.; Curigliano, G. The role of histone deacetylase inhibitors in metastatic breast cancer. The Breast 2018, 43, 130–134. [Google Scholar] [CrossRef] [PubMed]
  68. Guo, P.; Chen, W.; Li, H.; Li, M.; Li, L. The histone acetylation modifications of breast cancer and their therapeutic implications. Pathol. Oncol. Res. 2018, 24, 807–813. [Google Scholar] [CrossRef]
  69. Lee, H.; Zhang, P.; Herrmann, A.; Yang, C.; Xin, H.; Wang, Z.; Hoon, D.S.; Forman, S.J.; Jove, R.; Riggs, A.D.; et al. Acetylated stat3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation. Proc. Natl. Acad. Sci. USA 2012, 109, 7765–7769. [Google Scholar] [CrossRef]
  70. Lapidus, R.G.; Nass, S.J.; Butash, K.A.; Parl, F.F.; Weitzman, S.A.; Graff, J.G.; Herman, J.G.; Davidson, N.E. Mapping of er gene cpg island methylation-specific polymerase chain reaction. Cancer Res. 1998, 58, 2515–2519. [Google Scholar]
  71. Saenglee, S.; Jogloy, S.; Patanothai, A.; Leid, M.; Senawong, T. Cytotoxic effects of peanut phenolics possessing histone deacetylase inhibitory activity in breast and cervical cancer cell lines. Pharmacol. Rep. 2016, 68, 1102–1110. [Google Scholar] [PubMed]
  72. Parashar, G.; Capalash, N. Promoter methylation-independent reactivation of pax1 by curcumin and resveratrol is mediated by uhrf1. Clin. Exp. Med. 2016, 16, 471–478. [Google Scholar] [CrossRef] [PubMed]
  73. Beyer, S.; Zhu, J.; Mayr, D.; Kuhn, C.; Schulze, S.; Hofmann, S.; Dannecker, C.; Jeschke, U.; Kost, B.P. Histone h3 acetyl k9 and histone h3 tri methyl k4 as prognostic markers for patients with cervical cancer. Int. J. Mol. Sci. 2017, 18, 477. [Google Scholar] [CrossRef] [PubMed]
  74. Plewka, D.; Plewka, A.; Miskiewicz, A.; Morek, M.; Bogunia, E. Nuclear factor-kappa b as potential therapeutic target in human colon cancer. J. Cancer Res. Ther. 2018, 14, 516–520. [Google Scholar] [CrossRef]
  75. Pu, J.; Bai, D.; Yang, X.; Lu, X.; Xu, L.; Lu, J. Adrenaline promotes cell proliferation and increases chemoresistance in colon cancer ht29 cells through induction of mir-155. Biochem. Biophys. Res. Commun. 2012, 428, 210–215. [Google Scholar] [CrossRef] [PubMed]
  76. Jung, Y.J.; Lee, J.E.; Lee, A.S.; Kang, K.P.; Lee, S.; Park, S.K.; Lee, S.Y.; Han, M.K.; Kim, D.H.; Kim, W. Sirt1 overexpression decreases cisplatin-induced acetylation of nf-kappab p65 subunit and cytotoxicity in renal proximal tubule cells. Biochem. Biophys. Res. Commun. 2012, 419, 206–210. [Google Scholar] [CrossRef] [PubMed]
  77. Buhrmann, C.; Shayan, P.; Popper, B.; Goel, A.; Shakibaei, M. Sirt1 is required for resveratrol-mediated chemopreventive effects in colorectal cancer cells. Nutrients 2016, 8, 145. [Google Scholar] [CrossRef]
  78. Yaseen, A.; Chen, S.; Hock, S.; Rosato, R.; Dent, P.; Dai, Y.; Grant, S. Resveratrol sensitizes acute myelogenous leukemia cells to histone deacetylase inhibitors through reactive oxygen species-mediated activation of the extrinsic apoptotic pathway. Mol. Pharmacol. 2012, 82, 1030–1041. [Google Scholar] [CrossRef]
  79. Frazzi, R.; Valli, R.; Tamagnini, I.; Casali, B.; Latruffe, N.; Merli, F. Resveratrol-mediated apoptosis of hodgkin lymphoma cells involves sirt1 inhibition and foxo3a hyperacetylation. Int. J. Cancer 2013, 132, 1013–1021. [Google Scholar] [CrossRef]
  80. Kikuchi, H.; Mimuro, H.; Kuribayashi, F. Resveratrol strongly enhances the retinoic acid-induced superoxide generating activity via up-regulation of gp91-phox gene expression in u937 cells. Biochem. Biophys. Res. Commun. 2018, 495, 1195–1200. [Google Scholar] [CrossRef]
  81. Kai, L.; Samuel, S.K.; Levenson, A.S. Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting mta1/nurd complex. Int. J. Cancer 2010, 126, 1538–1548. [Google Scholar] [CrossRef] [PubMed]
  82. Xue, Y.; Wong, J.; Moreno, G.T.; Young, M.K.; Cote, J.; Wang, W. Nurd, a novel complex with both atp-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 1998, 2, 851–861. [Google Scholar] [CrossRef]
  83. Li, K.; Dias, S.J.; Rimando, A.M.; Dhar, S.; Mizuno, C.S.; Penman, A.D.; Lewin, J.R.; Levenson, A.S. Pterostilbene acts through metastasis-associated protein 1 to inhibit tumor growth, progression and metastasis in prostate cancer. PLoS ONE 2013, 8, e57542. [Google Scholar] [CrossRef] [PubMed]
  84. Dhar, S.; Kumar, A.; Li, K.; Tzivion, G.; Levenson, A.S. Resveratrol regulates pten/akt pathway through inhibition of mta1/hdac unit of the nurd complex in prostate cancer. Biochim. Biophys. Acta 2015, 1853, 265–275. [Google Scholar] [CrossRef] [PubMed]
  85. Harada, N.; Atarashi, K.; Murata, Y.; Yamaji, R.; Nakano, Y.; Inui, H. Inhibitory mechanisms of the transcriptional activity of androgen receptor by resveratrol: Implication of DNA binding and acetylation of the receptor. J. Steroid Biochem. Mol. Biol. 2011, 123, 65–70. [Google Scholar] [CrossRef]
  86. Chao, S.C.; Chen, Y.J.; Huang, K.H.; Kuo, K.L.; Yang, T.H.; Huang, K.Y.; Wang, C.C.; Tang, C.H.; Yang, R.S.; Liu, S.H. Induction of sirtuin-1 signaling by resveratrol induces human chondrosarcoma cell apoptosis and exhibits antitumor activity. Sci. Rep. 2017, 7, 3180. [Google Scholar] [CrossRef]
  87. Zadi Heydarabad, M.; Nikasa, M.; Vatanmakanian, M.; Azimi, A.; Farshdousti Hagh, M. Regulatory effect of resveratrol and prednisolone on mdr1 gene expression in acute lymphoblastic leukemia cell line (ccrf-cem): An epigenetic perspective. J. Cell Biochem. 2018, 119, 4890–4896. [Google Scholar] [CrossRef]
Medicines 06 00024 g001 550
Figure 1. Chemical structure of resveratrol.
Figure 1. Chemical structure of resveratrol.
Medicines 06 00024 g001
Medicines 06 00024 g002 550
Figure 2. Activation of tumor suppressor genes by resveratrol through promoter DNA hypomethylation. The CpG islands in the DNA promoter regions of the tumor suppressor genes are hypermethylated resulting in their silencing. De-methylation of these CpG islands by resveratrol results in the activation of transcription and the eventual expression of tumor suppressor genes such as the phosphatase and tensin homologue (PTEN), BRCA-1 and nuclear factor erythroid 2-related factor 2 (NRF2).
Figure 2. Activation of tumor suppressor genes by resveratrol through promoter DNA hypomethylation. The CpG islands in the DNA promoter regions of the tumor suppressor genes are hypermethylated resulting in their silencing. De-methylation of these CpG islands by resveratrol results in the activation of transcription and the eventual expression of tumor suppressor genes such as the phosphatase and tensin homologue (PTEN), BRCA-1 and nuclear factor erythroid 2-related factor 2 (NRF2).
Medicines 06 00024 g002
Medicines 06 00024 g003 550
Figure 3. Epigenetic regulation in triple negative breast cancers (TNBCs). TNBCs are characterized by activated STAT3 signaling, involving acetylated STAT3. ERα signaling in TNBCs is silenced through promoter DNA hypermethylation which might be related to STAT3 acetylation but the mechanisms remain unclear (and are therefore shown with a dotted line). Resveratrol is an effective inhibitor of STAT3 acetylation as well as ERα promoter DNA methylation. Restoration of ER-signaling makes TNBC cells sensitive to the ER-targeting therapy, tamoxifen.
Figure 3. Epigenetic regulation in triple negative breast cancers (TNBCs). TNBCs are characterized by activated STAT3 signaling, involving acetylated STAT3. ERα signaling in TNBCs is silenced through promoter DNA hypermethylation which might be related to STAT3 acetylation but the mechanisms remain unclear (and are therefore shown with a dotted line). Resveratrol is an effective inhibitor of STAT3 acetylation as well as ERα promoter DNA methylation. Restoration of ER-signaling makes TNBC cells sensitive to the ER-targeting therapy, tamoxifen.
Medicines 06 00024 g003
Table
Table 1. Epigenetic effects of resveratrol on tumor suppressors: mechanisms of their re-activation.
Table 1. Epigenetic effects of resveratrol on tumor suppressors: mechanisms of their re-activation.
Tumor SuppressorCancer TypeEffect of ResveratrolReference
BRCA-1BreastReduced promotor DNA methylation in vitro[36]
Reduced promotor DNA methylation in vivo[37]
NRF2BreastReduced promotor DNA methylation[38]
p53LymphomaInduced acetylation[73]
Prostate[75]
PAX1CervicalRegulation of histone acetylation[66]
PTENBreastReduced promoter DNA methylation[35]
ProstateAcetylation and activation[77]
RASSF-1αBreastReduced DNA methylation[42]

Share and Cite

MDPI and ACS Style

Farhan, M.; Ullah, M.F.; Faisal, M.; Farooqi, A.A.; Sabitaliyevich, U.Y.; Biersack, B.; Ahmad, A. Differential Methylation and Acetylation as the Epigenetic Basis of Resveratrol’s Anticancer Activity. Medicines 2019, 6, 24. https://doi.org/10.3390/medicines6010024

AMA Style

Farhan M, Ullah MF, Faisal M, Farooqi AA, Sabitaliyevich UY, Biersack B, Ahmad A. Differential Methylation and Acetylation as the Epigenetic Basis of Resveratrol’s Anticancer Activity. Medicines. 2019; 6(1):24. https://doi.org/10.3390/medicines6010024

Chicago/Turabian Style

Farhan, Mohd, Mohammad Fahad Ullah, Mohd Faisal, Ammad Ahmad Farooqi, Uteuliyev Yerzhan Sabitaliyevich, Bernhard Biersack, and Aamir Ahmad. 2019. "Differential Methylation and Acetylation as the Epigenetic Basis of Resveratrol’s Anticancer Activity" Medicines 6, no. 1: 24. https://doi.org/10.3390/medicines6010024

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop