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medicines
Review
Differential Methylation and Acetylation as the
Epigenetic Basis of Resveratrol’s Anticancer Activity
Mohd Farhan 1, Mohammad Fahad Ullah 2, Mohd Faisal 3, Ammad Ahmad Farooqi 4,
Uteuliyev Yerzhan Sabitaliyevich 5, Bernhard Biersack 6and Aamir Ahmad 7,*
1College of Basic Sciences, King Faisal University, Hofuf 400-Al Ahsa-31982, Saudi Arabia;
mfarhan@kfu.edu.sa
2Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk,
P.O. Box 741, Tabuk 71491, Saudi Arabia; m.ullah@ut.edu.sa
3Department of Psychiatry, University Hospital Limerick, Limerick V94 T9PX, Ireland; mohd.faisal@hse.ie
4Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 44000, Pakistan;
ammadfarooqi@rlmclahore.com
5Department of Postgraduate Education and Research, Kazakhstan Medical University KSPH,
Almaty 050004, Kazakhstan; e.uteuliyev@ksph.kz
6Organic Chemistry Laboratory, Department of Chemistry, University of Bayreuth, Universitaetsstrasse 30,
95447 Bayreuth, Germany; bernhard.biersack@yahoo.com
7Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama,
Mobile, AL 36604, USA
*Correspondence: aahmad@health.southalabama.edu
Received: 11 January 2019; Accepted: 11 February 2019; Published: 13 February 2019
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-1
α
(RASSF-1
α
) 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-
κ
B 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.
Keywords: resveratrol; epigenetic; methylation; acetylation
1. Introduction
Resveratrol (3,5,4
0
-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
–
7
]. It is now believed that resveratrol exhibits both antioxidant and prooxidant
Medicines 2019,6, 24; doi:10.3390/medicines6010024 www.mdpi.com/journal/medicines
Medicines 2019,6, 24 2 of 12
properties [
8
–
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.
Medicines 2019, 6, x FOR PEER REVIEW 2 of 12
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.
Figure 1. Chemical structure of resveratrol.
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–
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 [22–24].
A number of studies have recognized the effects of nutraceuticals, including polyphenol
resveratrol, on the epigenetic machinery in humans [25–35]. 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
Figure 1. Chemical structure of resveratrol.
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
–
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 [22–24].
A number of studies have recognized the effects of nutraceuticals, including polyphenol
resveratrol, on the epigenetic machinery in humans [
25
–
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
Medicines 2019,6, 24 3 of 12
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
µ
M, pterostilbene treatment was at a
7
µ
M 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
µ
M. 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.
Medicines 2019, 6, x FOR PEER REVIEW 3 of 12
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.
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).
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-
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).
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
Medicines 2019,6, 24 4 of 12
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
(17
β
-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
–
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-1
α
(RASSF-1
α
), Adenomatous Polyposis Coli (APC) and Cyclin D2 (CCND2).
An inverse relationship between serum resveratrol levels and RASSF-1
α
methylation was observed, i.e.,
when resveratrol levels increased, the methylation of RASSF-1
α
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
Medicines 2019,6, 24 5 of 12
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
–
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
–
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 ER
α
gene in tumor cells is
Medicines 2019,6, 24 6 of 12
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 ER
α
[
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 ER
α
gene promoter DNA methylation
(Figure 3). This resulted in the increased expression of ER
α
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.
Medicines 2019, 6, x FOR PEER REVIEW 6 of 12
[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.
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.
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
Figure 3.
Epigenetic regulation in triple negative breast cancers (TNBCs). TNBCs are characterized by
activated STAT3 signaling, involving acetylated STAT3. ER
α
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 ER
α
promoter DNA methylation. Restoration of ER-signaling makes
TNBC cells sensitive to the ER-targeting therapy, tamoxifen.
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-
κ
B 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-
κ
B p65 subunit leads to
the activation of the NF-
κ
B 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-
κ
B 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.
Medicines 2019,6, 24 7 of 12
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 b
558
[
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.
Table 1. Epigenetic effects of resveratrol on tumor suppressors: mechanisms of their re-activation.
Tumor Suppressor Cancer Type Effect of Resveratrol Reference
BRCA-1 Breast
Reduced promotor DNA methylation
in vitro [36]
Reduced promotor DNA methylation
in vivo [37]
NRF2 Breast Reduced promotor DNA methylation [38]
p53 Lymphoma Induced acetylation [73]
Prostate [75]
PAX1 Cervical Regulation of histone acetylation [66]
PTEN Breast Reduced promoter DNA methylation [35]
Prostate Acetylation and activation [77]
RASSF-1αBreast Reduced DNA methylation [42]
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
µ
M 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.
Medicines 2019,6, 24 8 of 12
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-
κ
B 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.
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