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Mol Nutr Food Res. Author manuscript; available in PMC 2017 June 01.
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Published in final edited form as:

Mol Nutr Food Res. 2016 June ; 60(6): 1264–1274. doi:10.1002/mnfr.201500822.

Molecular mechanisms of flavonoids in melanin synthesis and

the potential for the prevention and treatment of melanoma
Feng Liu-Smith1,2 and Frank Meyskens1,2,3,4
1Department of Epidemiology, Chao Family Comprehensive Cancer Center, UC Irvine, Irvine, CA
92697
2Department of Medicine, Chao Family Comprehensive Cancer Center, UC Irvine, Irvine, CA
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92697
3Department of Public Health, Chao Family Comprehensive Cancer Center, UC Irvine, Irvine, CA
92697
4Department of Biological Chemistry, Chao Family Comprehensive Cancer Center, UC Irvine,
Irvine, CA 92697

Abstract
Flavonoids are becoming popular nutraceuticals. Different flavonoids show similar or distinct
biological effects on different tissues or cell types, which may limit or define their usefulness in
cancer prevention and/or treatment application. This review focuses on a few selected flavonoids
and discusses their functions in normal and transformed pigment cells, including cyanidin,
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apigenin, genistein, fisetin, EGCG, luteolin, baicalein, quercetin and kaempferol. Flavonoids
exhibit melanogenic or anti-melanogenic effects mainly via transcriptional factor MiTF and/or the
melanogenesis enzymes tyrosinase, DCT2 or TYRP-1. To identify a direct target has been a
challenge as most studies were not able to discriminate whether the effect(s) of the flavonoid were
from direct targeting or represented indirect effects. Flavonoids exhibit an anti-melanoma effect
via inhibiting cell proliferation and invasion and inducing apoptosis. The mechanisms are also
multi-fold, via ROS-scavenging, immune-modulation, cell cycle regulation and epigenetic
modification including DNA methylation and histone deacetylation. In summary, although many
flavonoid compounds are extremely promising nutraceuticals, their detailed molecular mechanism
and their multi-target (simultaneously targeting multiple molecules) nature warrant further
investigation before advancement to translation studies or clinical trials.
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Keywords
Flavonoids; Luteolin; melanoma; melanogenesis; prevention

Co-Correspondence: Feng Liu-Smith, PhD, 256A Irvine Hall, Department of Epidemiology, Chao Family Comprehensive Cancer
Center, University of California Irvine, Irvine, CA 92697, [email protected].
Frank L. Meyskens, MD, Professor of Medicine, Biological Chemistry, Public Health, and Epidemiology, Department of Population
Health and Disease Prevention, Director Emeritus, Chao Family Comprehensive Cancer Center, University of California, Irvine,
[email protected]
Conflicts of interests
These authors state no conflict of interests.
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1. Introduction
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Flavonoids are a large group of polyphenolic compounds found in a wide range of

vegetables and medicinal herbs; so far more than 5000 compounds have been identified [1].
These compounds exhibit a broad range of anti-tumor, anti-allergic, anti-inflammation, anti-
fungal and anti-viral functions and have attracted much attention in the chemoprevention and
cancer treatment fields. Because they are easily available nutrients in regular diets and as
they have exhibited high pharmaceutic potential in preclinical studies, many of these
compounds have become popular as nutraceuticals. There have been many publications on
flavonoids and their potential roles in the management of cancer; however, information
about these compounds vis-a-vis the pathogenesis of melanoma have been limited [2]. As
flavonoids show dramatic cell line and tissue specificities [3, 4], it is incumbent that we
examine what has been done to date both mechanistically and preclinically before
proceeding to translational studies of melanoma.
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Flavonoids include several major groups of compounds with the shared core backbone
structure of flavan: flavones, flavonols (3-hydroxyflavone), flavanols, isoflavones and
anthocyanidins (Fig. 1A), all with different side group modifications [5, 6] . The main
structure of flavan is comprised of three rings: A, B, and C rings (Fig 1A). The above major
groups of flavonoids differ on their modification of side groups on these rings. These side
groups play crucial roles in the function of these compounds as the side modification can
produce very different activities. Table 1 lists the most commonly used flavonoids that have
been tested in melanoma models and their major dietary sources. The most informative data
have been derived from these compounds therefore this review will focus on these listed
compounds and their possible molecular mechanisms of action in the pathogenesis of
melanoma. However this is a limited list as there are many more flavonoids that have been
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studied in melanocytic cell lineage, including rutin, robinetin, rhamnetin, naringin, chrysin,
ipriflavone, tangeritin and more, and some derivatives of these compounds [7–9].

Cutaneous melanomas arise from skin melanocytes, a cell type that is specialized in
synthesizing melanin which contributes to skin color and protection against solar UV (ultra-
violet) radiation. Skin color is an important part of beautification [10]; for example, a tan
color has become desirable for white skinned individuals (Caucasians) while a lighter color
has become more desirable for darker-skinned Asian individuals, especially women.
Therefore the skin care industry has been seeking various methods to safely manipulate skin
color. As a consequence, there are many studies using flavonoids as skin-whitening agents
[11], as listed in Table 1. This review attempts to summarize the known effect of flavonoids
in melanogenesis and melanomagenesis and their potential molecular mechanisms. As is
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revealed in this short review, it is apparent that majority of the pigmentation and anti-
melanoma studies have been performed in vitro and/or in B16 mouse melanoma cell lines,
indicating that in vivo studies and studies with human cells are still needed to enable clinic
use of these compounds.

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2. Flavonoids function in melanogenesis

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As listed in Table 1, cyanidin, hesperetin, apigenin, genistein and fisetin all exhibited
melanogenic effect, i.e., stimulated melanin synthesis. On the other hand, EGCG or other
catechins, hesperidin, luteolin, baicalein and kaempferol all inhibited melanin synthesis. For
quercetin, two studies showed stimulatory effect and one showed an inhibitory effect. We
have listed cell lines (mouse or human) used in each study because the regulation of melanin
syntheses may be different in human and mouse normal and malignant cells by these
compounds. Indeed, caution when evaluating these compounds across species types needs to
be the order of the day.

Pigmentation is a very complex biochemical process involving more than 300 loci in mice,
according to International Federation of Pigment Research Society website (http://
www.espcr.org/micemut/). Most of these loci have corresponding orthologues with human
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genes. Figure 2 lists the major pathway showing a few key genes in this process. Mainly,
upon stimulation by the α-melanocytes stimulating hormone (α-MSH), MC1R
(Melanocortin Receptor 1) transmits a signal to cAMP-PKA (cyclic AMP and Protein
Kinase A) [12] , whose activation leads to enhanced expression of the melanocytes master
transcriptional factor MITF (Microphthalmia Transcription Factor) which in turn activates
expression of the major melanogenic enzymes tyrosinase, dopachrome tautomerase (DTC,
also known as tyrosine-related protein 2, TYRP-2) and tyrosine-related protein 1 (TYRP-1)
via binding to E boxes on their promoters [13–16]. Agouti signaling protein (ASIP)
antagonizes the functions of α-MSH and inhibits the melanin synthesis pathway (Fig. 2)
[17]. This schema is oversimplified as melanins exist as two classes: eumelanin and
pheomelanin and their synthesis share some regulatory features but differ in others. Most of
melanogenesis effects of flavonoids have been targeted to this simplified scheme. As shown
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in Fig. 2, hesperidin and catechins (including EGCG) inhibited MITF protein accumulation
[18, 19]; EGCG in addition inhibited tyrosinase accumulation [19, 20]. Hesperetin which
stimulated melanogensis, on the other hand, enhanced MITF accumulation; the upstream
signal was not investigated [21]. Baicalein, a depigmenting agent, inhibited MITF
accumulation via ERK1/2- phosphorylation mediated degradation [22]. Luteolin, genistein,
kaempferol and quercetin all targeted tyrosinase directly or indirectly [23–26]. Apigenin did
not target tyrosinase, rather it targeted TYRP-2/DCT and TYRP-1, perhaps via p38 mitogen
activating protein kinase [27].

Note that even though luteolin increased tyrosinase protein accumulation in B16 melanoma
cells, this compound in the end inhibited melanin synthesis and several studies suggest that
it is a skin-whitening agent [23, 28]. This may be because luteolin actually inhibited
tyrosinase activity and the upstream α-MSH mediated cAMP signaling [28]. Results from
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our lab have revealed that luteolin dramatically up-regulated ASIP (Agouti-signaling
protein) at mRNA level (17.0 fold of increase as compared to untreated control cells) in
human A375 melanoma cells (data not shown). This action may reflect a novel layer of
regulation by luteolin for the melanogenesis pathway, but will require extensive studies to
validate. As shown in Figure 2, ASIP binds to MC1R and inhibits α-MSH-mediated
cAMP/PKA activation and hence inhibits downstream melanin synthesis [17] , ASIP
polymorphisms are associated with human pigmentation phenotypes and melanoma risk [29,

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30]. To date, ASIP is not known to regulate pigmentation via an autocrine route; a previous
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study showed ASIP expression at the mRNA and protein level in melanoma cell lines [31],
which is consistent with our unpublished results, suggesting this protein may have the
potential to exhibit autocrine function.

Of importance is that although some compounds have similar structures, they show drastic
differences on melanogenesis regulation. For example, in comparing apigenin and luteolin,
there is only one extra hydroxyl group in luteolin (Fig. 1B), yet, apigenin stimulated, while
luteolin inhibited, melanin synthesis. It is speculated that the extra hydroxyl group in
luteolin played a crucial role in determining some specificities of this compound. Also,
compared to luteolin, quercetin has an extra hydroxyl group on the C ring, which apparently
also results in different cellular functions (Fig. 1B and Table 1). This differential function of
structurally similar flavonoids is not only observed in the melanogensis pathway, it has also
been observed in cardiovascular and cancer-related pathways as well [32].
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3. Flavonoids function in melanoma prevention. treatment and metastasis

prevention
Flavonoids have been widely used as experimental chemoprevention and chemotherapy
agents in many different cancer types including breast, prostate, pancreas, bladder, lung and
colon cancer [33–35]. Epidemiological studies show that estimated dietary intake of total
flavonoids (most of the time it is not specified) is usually (but not always) inversely
correlated with cancer risk [36–38]. Carefully designed cancer prevention trials (including
melanoma) are currently lacking. Below we summarize the potential molecular mechanisms
of flavonoids and their activities in anti-oxidant, anti-inflammation and immune modulation,
anti-proliferation, anti-angiogenesis, apoptosis induction and potential epigenetic
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modification, with most studies executed in vitro, a few in mouse; and some were
epidemiological observations.

3.1 Flavonoids as reactive oxygen species (ROS) scavenger for melanoma

Numerous studies have showed that many flavonoids are potent antioxidants, therefore they
may serve as effective scavengers of reactive oxygen species [39, 40]. Because excessive
ROS cause many problems including DNA, lipid and protein damage and aberrant cellular
signaling, flavonoids are apparently protective agents in such conditions.

A number of in vitro assays have been developed to measure the radical scavenger activities
in vitro, including 2,2-diphenyl-1-picrylhydrazyl radical (DPPH assay), ferric reducing
antioxidant power (FRAP assay), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate)
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radical cation (TEAC assay), 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical

(ABTS(·+) assay) (ABTS assay), Folin-Ciocalteu reducing capacity (FC
assay),electrochemical total reducing capacity, and hypoxanthine/xanthine oxidase system
coupled with nitroblue tetrazolium (NBT) reduction (NBT/XO) [28, 41, 42]. All flavonoids
listed in Table 1 showed some degrees of free radical scavenger activities, with luteolin and
quercetin among the most potent antioxidants in the category [4, 43]. For example, luteolin
showed dose-dependent antioxidant activity in DPPH and NBT/XO assays in a cell-free

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system, as well as in B16 cells by H2DCF-DA (dihydrodichlorofluorescein diacetyl)-based

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intracellular ROS assays [28].

The detailed molecular mechanisms of flavonoids remain to be clarified but can be

summarized into three major categories:

a. As chelators for redox-potent transition metal ions, which include Cd2+ Fe2+, Co2+,
Ni2+, Cu2+, Cr3+ and Zn2+ [44, 45]. These metals cause an ROS increase via
different mechanisms and some are potent carcinogens. The metal binding sites for
flavonoids are usually adjacent hydroxyl and/or ketone side groups. For example,
the potential metal binding site for apigenin is between the 5-OH group of A ring
and the ketone group on C ring (Fig 1B, boxed).

b. Reacting directly with free radicals via their free hydroxyl group(s) and quench
these activities [42]. For example, quercetin scavenges superoxide free radicals
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mainly function through 3’4’-dihydroxy groups on the B ring [46].

c. Modulating multiple cellular anti-oxidant systems which re-establish redox balance

in cells after oxidative stress.

These functions are not mutually exclusive. In a previous review we summarized the source
of ROS in melanoma [47], including mitochondria, NADPH oxidases, nitric oxidases,
lipoxygenase, cyclooxygenase 2 (COX-2) and melanosomes. These ROS sources are
regulated by major redox transcriptional regulators NRF2 (nuclear factor erythroid 2 [NF-
E2]-related factor 2), and the AP-1 family members [48–50], among other factors [51].
NRF2 is an important target for flavonoids as it is also the master transcriptional factor for
redox regulation [52]. Luteolin was initially found to be a NRF2 inhibitor in lung carcinoma
A549 cells [53]; however, in colorectal and prostate cancers and in neuronal cells luteolin
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activated NRF2 [54–56]. This compound also enhanced NRF2 translocation into the nucleus
where it functions as a transcriptional activator in neuronal cells [57]. Furthermore, luteolin
inhibited Cr(VI)-induced malignant cell transformation of human lung epithelial cells by
targeting multiple ROS mediated cell signaling pathways [58]. Luteolin inhibited NRF2
target glutathione S-transferase in SK-Mel-28 human melanoma cells [59]; we found that
luteolin inhibited NRF2 protein accumulation at 30 μM but stimulated NRF2 accumulation
at 8 μM in SK-Mel-28 cells (Liu-Smith et al., unpublished data). These studies suggest that
luteolin exhibits different effects on the same target gene in different cell lines, or even
opposite effects on the same target at different concentrations. On the other hand, apigenin
showed more consistent effects in different cell lines or in different studies: apigenin
stimulates NRF2 activities in prostate cancer, mouse skin epidermal JB6 P+ cells,
hepatocellular carcinoma HEPG2-C8 cells and primary hepatocytes [56, 60–63], via MAPK
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pathway, epigenetic modification of NRF2 promoter, or PI3K pathway. Quercetin shows

similar NRF2-enhancing effect as apigenin, with the end results of activating NRF2-
regulated antioxidant genes including heme-oxygenase 1, NAD(P)H Dehydrogenase,
Quinone 1(NQO1) and genes for glutathione synthesis [64–67]. Genistein and EGCG also
induced NRF2 in different cellular background for invoking a protective antioxidant
mechanism [68–70]. For other targets, baicalein enhanced Cox-2 expression [71], but
luteolin, apigenin, genistein suppressed its expression or function [72–75]. Luteolin,
quercetin and apigenin also exhibit AP-1 inhibitory effects [76–78].

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Mitochondria and ROS-generating enzymes can also be targets for flavonoids; however,
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published data show that flavonoids serve either as ROS scavengers or ROS stimulators. In
A375 cells apigenin directly targeted and compromised the oxidative phosphorylation
system in mitochondria and induced ROS levels which led to cell death [79]. Similarly,
baicalein also induced ROS in B16 cells, possibly via12-lipoxygenase [48]; and quercetin
increased ROS levels in DB-1 melanoma cells via inhibiting bio-reduction capacity, namely
the glutathione-S transferase and NQO1 levels [80]. On the other hand, luteolin directly
inhibited xanthine oxidase activity in a dose-dependent manner and reduced cellular ROS
levels in B16 cells [28]. As all antioxidants have the potential to be converted into pro-
oxidants, it is not surprising to see these conflicting results. Our own experiments with
luteolin showed dose-dependent differential stimulating and inhibitory results on NRF2
(described above) accumulation in the same cell line, we speculate that some of the
flavonoids may require a specific dose range to act as antioxidants, or else they may
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stimulate ROS production. Despite much evidence that flavonoids serve as ROS scavengers,
the antioxidant property is not the only mechanism for their protective roles for human cells
[81]. Next we will discuss their other cellular roles.

3.2 Flavonoids function in anti-inflammation and immune-modulation in melanoma

There is strong evidence that inflammation and immune suppression play important roles in
melanoma etiology, progression, and even prognosis: 1) the major environmental risk factor
Ultra-Violet (UV) radiation causes skin immune suppression [82] , 2) melanoma tumors
contain large amount of infiltrated immune cells [83] and 3) BRAF inhibitor-mediated
immunosuppression is a reason for therapeutic failure [84]. Also inflammation exhibits an
intrinsic correlation with oxidative stress which is highly elevated in melanoma [85]. For all
these aspects, the anti-inflammatory properties of flavonoids in preclinical have shown a
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potentially important impact on melanoma etiology, prevention, and treatment outcomes.

Briefly, flavonoids modulate inflammatory effects through a few key mediators in melanoma
and skin tissues: AP-1 family transcriptional factors [86], NFκB [87], STAT3 [88] and nitric
oxidases (mainly iNOS and nNOS) [89, 90].. AP-1 and NFκB are able to up-regulate
cytokine expression such as IL-8 [91, 92]; as stated above, AP-1 can be inhibited by luteolin,
quercetin and apigenin [76–78]. Luteolin was shown to promote proteasome-mediated
degradation of STAT3 and thus blocked the inflammatory signals from cytokines such as IL6
and IL10 [93]. Quercetin, on the other hand impaired STAT3 nuclear localization via
altering its phosphorylation [94]. EGCG prevents UV-induced immunosuppression via a
mechanism that involves production of IL-12. In IL-12 knockout mice or mice injected with
anti-IL-12 antibodies, EGCG lost its ability to inhibit UV-induced immune -suppression
[95]. Nitric oxide (NO) plays an important role in the melanoma inflammatory
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microenvironment which promotes tumor growth and metastasis; iNOS-expression in

melanoma is negatively correlated with patient survival [96]; and nNOS is up-regulated in
melanoma and is a potential target for melanoma therapy [90]. Paracrine NO production led
to decreased CXC chemokine ligand 10 (CXCL10) levels which resulted in less
inflammatory tumor microenvironment in melanoma patients and WM1727A, A375 and
SB2 melanoma cell lines [96]. Flavonoids exhibit complex reactions with NO. In cell free
system flavonoids have NO-scavenger activity but may generate superoxide at the same time
[97]; under oxidative stress flavonoids may play an anti-inflammation role via inhibiting

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iNOS or inhibiting the NFκB pathway [97]. Thus it is likely that the impact of flavonoids on
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NO levels (perhaps also ROS levels) is dependent on the flavonoid type, concentration and
cellular conditions such as expression levels of iNOS.

3.3 Flavonoids anti-proliferative, apoptotic induction and anti-metastatic activities

Flavonoids exhibit anti-proliferative and anti-apoptotic effects via HGF/SF-Met signaling,
MAPK pathway, cell cycle regulation, differentiation induction and PI3K-AKT pathway.
Like their function in melanogenesis, different flavonoids exhibit different effects on their
cellular targets -which are quite diverse.

Flavonoids inhibited xenografted B16-BL6 mouse melanoma growth in the decreasing order
of effectiveness: EGCG, apigenin, quercetin, with the latter two compounds showing similar
effects as tamoxifen [98]. EGCG inhibited colony formation in soft-agar [99], possibly by
inhibiting cyclin D1, CDK2 and PCNA (Proliferating Cell Nuclear Antigen) while inducing
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p21waf1/cip1 and p27kip1, and promoting apoptosis [100]. EGCG reduced MITF protein
accumulation via ERK1/2-independent mechanism [19], which may also contribute to its
anti-proliferation effect because MITF is generally a melanoma survival gene [101].
Similarly, apigenin induced G2/M cell cycle arrest via inhibiting CDK1 activity [102],
which may contribute to its anti-melanoma activity in vivo on xenografted B16 cells [98].
Cyanidin glucopyranoside induced B16 differentiation via up-regulating cAMP, tyrosinase
expression, and the differentiation marker MART-1 [103]. Both EGCG and quercetin
inhibited HGF/SF-Met signaling, a key regulator of melanoma migration and invasion [104,
105]. Fisetin inhibited 451Lu cell proliferation via disrupting the β-catenin/MITF signaling
pathway [106]; also inhibited melanoma cell invasion and metastasis through inhibiting the
epithelial to mesenchymal transition in a three-dimensional skin model and in a xenografted
mice model [107, 108]. Combination treatment of xenografted A375 and SK-Mel-28 tumors
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with fisetin and RAF inhibitor Sorafenib showed greater reduction in tumor growth than
single compounds or control mice due to multiple mechanisms, including induction of
apoptosis, inhibition of proliferation and angiogenesis, and inhibition of the MAPK and
PI3K pathways [109].

Overall, whether flavonoids directly target the affected genes is not clear; what is clear is
that all these compounds, more or less, show an anti-proliferation and/or anti-metastatic
effect against melanoma (Table 1). Recent development in nanotechnology have made
flavonoids much more effective in targeting melanoma cells both in vitro and in vivo [110–
112]; therefore in the near future we may witness clinical use of these promising natural
compounds. However, whether individual compounds delivered by nanoparticles needs to be
assessed as drugs first is an issue that has not yet been addressed by regulatory bodies.
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3.4 Flavonoids in epigenetic modification: histone acetylation and DNA methylation

The diverse targets of flavonoids may be directly related to their diverse structures [113].
However, there may be a substantial contribution for the epigenetic modification function of
flavonoids. Increasing evidence suggests that many flavonoids are able to regulate gene
expression via epigenetic approaches including histone modification, DNA methylation and
miRNA/lncRNA (microRNA and long non-coding RNA) [114]. These epigenetic

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modifications may affect much diversified target genes. Histones can be modified by
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acetylation and methylation via histone acetyl transferase (HAT), histone deacetylase
(HDAC), histone methyl transferase (HMT) and histone demethylase (HDM) [115]. DNA
can be modified by methylation via DNA methyl transferases [114]; how DNA is de-
methylated is still not clear and is under intensive investigation [116]. The epigenetic
modification functions of most flavonoids from Table 1 are listed in Table 2, with most data
obtained from cell types other than melanoma. Only limited studies were performed in
melanoma cell lines. DNA methyl transferases (DNMTs), HDACs and HAT are common
targets of flavonoids in melanoma, and these enzymes affect the expression of tumor
suppressors such as p21CIP1 and p16INK4A [117, 118]. In several human melanoma cell
lines, green tea polyphenols (mixture of epicatechin monomers) showed significant
inhibitory effect on HDAC activities and class I HDAC proteins, and promoted HAT activity,
resulting in proliferation inhibition and cell killing [117, 119]. This mechanism may explain
a previous observation that EGCG up-regulated p16INK4A, p27KIP1 and p21CIP1 protein
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levels in A375 and Hs294t melanoma cells [100], as it was well known that these tumor
suppressor genes were subjected to epigenetic silencing in melanoma cells [120–122].

4. Conclusions
Flavonoids are widely available from food and herbs, and have the potential to become
therapeutic agents with minimum toxicity. However, not many (if any) clinical trials have
been done to establish the profile of flavonoids and the toxicity curve at the doses required to
prevent or treat cancer in humans, more in vivo studies and human trials are needed to
explore their clinical activities. Although it is difficult to pinpoint each compound’s
intracellular target, their overall effectiveness should be noted. Lack of specificity may be
because they are able to simultaneously target many different genes, but that may be the
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exact reason for their functional versatility. Also, like other chemical compounds, flavonoids
are subjected to metabolism and the metabolites may also be active components in vivo,
rendering it even more difficult to identify a single target. Investigators and the public should
respect this diversity of action and not to be limited by the “targeted therapy” mantra in the
exploration of clinical usefulness of nutraceuticals.

Acknowledgments
FLS is supported by NIH/NCI K07 award (CA160756) and FLM by the Waltmar Foundation.(to FLS and FLM)

Abbreviations
cAMP-PKA cyclic AMP-protein kinase A
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DTC2 dopachrome tautomerase

TYRP-1 tyrosine-related protein 1

EGCG epigallocatechin gallate

MiTF microphthalmia transcription factor

NRF2 nuclear factor erythroid 2 [NF-E2]-related factor 2

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ROS reactive oxygen species

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DNMT DNA methyl transferases

NO nitric oxide

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MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res. 2005; 11(19 Pt 1):
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7033–41. [PubMed: 16203797]

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Figure 1. Skeleton structures of major flavonoids and luteolin, apigenin and quercetin
A: Six main classes of flavonoids are listed, which are the focus of this review. Locations of
three rings (A, B and C) are labelled on flavan which are the same for other compounds. B:
Structure comparison of luteolin, apigenin and quercetin. The different side groups are
circled in luteolin structure. The boxed side groups in apigenin show a typical structure that
is able to bind metal ions. Comparing these three popular compounds which sometimes
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show opposite effects on melanogenesis may provide some hints on how each side group
functions biologically.
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Figure 2. Molecular mechanisms of flavonoids on melanin synthesis

The current understanding of melanin synthesis follows the cAMP-PKA-MITF-tyrosinase
scheme, in which MITF serves as the master transcriptional factor activating tyrosinase,
DCT and TYRP-1, and receives signals from MC1R. Inhibitory or stimulatory effects of
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each compound are listed in the scheme with references discussed in the text.
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Table 1

An Overview of Flavonoids: Sources and Functions

Function in melanoma prevention/

Category Major Dietary Sources Compounds Pigment Synthesis Reference Reference cell line treatment Reference

Anthocyanidin Berries, grapes Cyanidin Increase [103] Human Anti-proliferation [123]

Anti-metastasis, anti- proliferation,

Flavanol Chocolate, cherry, green tea
EGCG/Epicatechin Inhibition [19, 20] apoptosis, immunomodulation [95, 124, 125]
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Hesperetin Increase [21, 126] Human, Mouse No known effect [8]

Flavanone Citrus fruits
Hesperidin Inhibition [18] Human, Mouse No report

Apigenin Increase [27, 127] Mouse Anti-proliferation, anti-metastasis [98]

Celery, parsley
Flavone Luteolin Inhibition [23] Mouse Anti-proliferation, anti-metastasis [128, 129]

Baikal skullcap (medicinal herb) Baicalein Inhibition [22] Mouse Anti-proliferation [48, 130]

Increase [25] Human [98]

Increase [131] Mouse

Onions, apples, Kale, Leek, broccoli
Flavonol Quercetin Inhibition [132] Mouse Anti-proliferation, anti-metastasis
Strawberry
Fisetin Increase [7, 133] Human Mouse Anti-proliferation, anti-metastasis [107, 108,134]

Kaempferol Inhibition [26] Mouse Anti-proliferation (G2/M arrest) [102]

Daidzein No effect [24] Mouse, Human Anti-proliferation, anti-metastasis [24, 135]

Isoflavone Soybean
Genistein Increase [24] Mouse, Human Anti-proliferation [135, 136]

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Table 2

Known functions of flavonoids in epigenetics

Flavonoids Targets Reference

EGCG/Epicatechin DNMT, HDAC3, HAT, [137–139]

Hesperetin DNMT [140]

Apigenin DNMT, HDAC

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[140, 141]

Luteolin DNMT [140]

Baicalein DNMT [142]

Quercetin DNMT1, HDAC, HAT [143, 144]

Kaempferol HDAC [145]

Daidzein DNMT [140, 146]

Genistein DNMT [118, 140,146, 147]

DNMT: DNA methyl Transferase; HDAC: Histone Deacetylase; HAT: Histone acetyl transferase.

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