Review ISSN 1993-6842 (on-line); ISSN 0233-7657 (print)

Biopolymers and Cell. 2016. Vol. 32. N 6. P 409–417

doi: http://dx.doi.org/10.7124/bc.000937

UDC 577.218

A potential role of hydrogen sulfide (H2S) in regulation of the Ras-ERK

signaling-dependent transcription of DNA methyltransferases
T. A. Nikitina
Oles Honchar Dnipropetrovsk National University
72, Gagarin Av., Dnipropetrovs’k, Ukraine, 49050
tatyana-dudkova@mail.ru

The Ras-ERK cell signaling regulates transcription of DNA methyl-transferases (DNMTs). A role of H2S in
regulation of the Ras-ERK signaling activity and DNMTs expression has also been shown. Here we propose
a hypothesis that H2S regulates the Ras-ERK signaling-dependent DNMTs transcription. Oxidative stress, li-
pid metabolism, protein sulfhydration, nitrosylation and nitration are the main targets of regulation by H2S.
These cell processes are important for the post-translational modifications (PTMs) of the Ras-ERK signaling
pathway enzymes. We provide evidence for the dependence of DNMTs transcription on the PTMs of the en-
zymes of the Ras-ERK signaling pathway regulated by H2S.
K e y w o r d s: Ras-ERK cell signaling, DNA methyltransferases, H2S

Introduction

DNMTs are the group of enzymes that catalyze

methylation of cytosine nucleic acids in CpG dinu-
cleotide sequences of DNA. The product of this re-
action is 5-methylcytosine (Fig. 1) [1, 2]. The main
substrate of DNMTs is
S-adenosinemethionine (SAM) converted to
S-adenosinehomocysteine (SAH) as a result of the
reaction. SAH is a DNMTs concurrent inhibitor that
is why SAH utilization is important for the DNMTs
activity [3]. The methionine cycle is a cascade of re-
actions which provides the SAM biosynthesis and
SAH utilization [3, 4].
In the last decade more attention has been paid to
the metabolite of the methionine cycle hydrogen sul-
fide (H2S). H2S is biosynthesized by many organ-
isms, including humans. There are three basic routes
Fig. 1. A – Schematic representation of the conversion of cyto-
of H2S biosynthesis in humans: 1) enzymatic con- sine to 5-methylcytosine (the author). B – Schematic representa-
densation of two homocysteine molecules (30 % of tion of the main enzymatic routes of H2S biosynthesis in humans
total H2S production); 2) enzymatic condensation of (the author).

© 2 016 T. A. Nikitina; Published by the Institute of Molecular Biology and Genetics, NAS of Ukraine on behalf of Biopolymers and Cell.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
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T. A. Nikitina

cysteine and homocysteine (25–70 % of total H2S kinases С, α, βI, βII, δ, γ, η, ζ μ and acetylation by
production); 3) enzymatic cysteine conversion to Tip60, HAUSP, UHRF1, HDAC1, PCNA as the
H2S, pyruvate and NH4+. The second reaction is main PTMs of DNMT1 [32–33].
catalyzed by Cystationine-beta-Synthase (CBS) oth- So, DNMTs are under a tight control of cell sig-
ers are catalyzed by Cystathionine-gamma-Lyase naling at the transcriptional and protein biosynthesis
(CSE) [5, 6].It is now known that H2S is a substrate levels. That is why the great prospects are opened for
for post-translational modification of a protein, researches to affect DNA methylation through cell
called sulfhydration [7]. Furthermore, H2S is an im- signaling pathways. Thus, the researches have a
portant element of the antioxidant system [8], as great potential to affect DNA methylation through
well as a regulator of the lipid [9–12] and NO me- cell signaling pathways.
tabolism [13–16].
We hypothesized an important role of H2S in the General description of the DNMTs
Ras-ERK signaling pathway regulation of the transcription regulation by the Ras-ERK
DNMTs transcription through above-mentioned signaling
mechanisms. Indeed, there are a lot of studies on the ERK ½ (extracellular signal-regulated kinase), also
Ras-ERK signaling and DNMTs transcription regu- known as p42 ⁄p44MAPK or MAPK1 and MAPK3,
lation by H2S upon the oxidative stress conditions are isoforms of MAPK (mitogen-activated protein-
[17–19]. We also pointed out to the proteine sulfhy- kinases) belonging to the family of proteins-trans-
dration and nitrosylation as well as lipid metabolism duced signals from the plasma membrane to the nu-
as new potential regulation targets of H2S important cleus. The activation of plasma membrane receptors
for the Ras-ERK dependent DNMTs transcription. results in induction of the Ras-Raf-MEK-ERK phos-
phorylation cascade, which leads to ERK nucleus
General characterization of the DNMTs translocation and transcription initiation. However,
expression regulation besides their action in the nucleus, ERK are also im-
There are three active DNMTs in humans – DNMT1, potent cytoplasmic signaling proteins [34].
DNMT3a, DNMT3b. DNMT1 catalyzes methyla- There is a line of in vitro studies on the role of the
tion per sample, saving methylation pattern during Ras-ERK signaling regulation of the DNMTs tran-
cell division. DNMT3a/3b are de novo methyltrans- scription [35–39]. The first studies were carried out
ferases. Two isoforms, DNMT2 and DNMT3L, with the human adrenocortical cancer and mouse
show a very weak activity [20, 21]. The main func- embryonal teratocarcinoma cell lines [35, 36]. In the
tion of DNA methylation is down-regulation of the experiment with adrenocortical cell line bearing am-
gene expression. It is important for X-chromosome plified ras gene, the authors demonstrated the Ras
inactivation, gene imprinting, and cell-specific gene dependent DNMT1 expression at the transcriptional
expression [22–24]. level [35]. The experiments with mouse embryonal
The regulation of DNMTs is performed at the teratocarcinoma showed similar results [36]. Both
transcriptional and post-transcriptional levels. There studies highlighted the AP-1 transcriptional regula-
is an evidence of Sp1 and Sp3 transcriptional regula- tion of the dnmt1 gene promoter. It was shown that
tion of DNMT1, DNMT3a, DNMT3b [25, 26], the gene promoter of dnmt1 bears AP-1 transcrip-
DNMT3b down-regulation by FOXO3a and tional sites [37].
DNMT3a down-regulation by p53 [27, 28]. Most of Besides the dnmt1 expression regulation through
the studies are dedicated to the DNMT1 regulation. AP-1 transcriptional sites by ERK, there are two in
It is well known that the transcription of DNMT1 is vitro issues dwelling on the role of ERK in the tran-
regulated by Ras/AP-1 and RB/E2F signaling [29– scriptional regulation of DNMT 3a and DNMT3b
31]. It is also possible to observe phosphorylation by employing unknown mechanisms [38, 39]. The ex-

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 The role of H2S in the DNMTs transcription regulation

periments with TGF-b1 treatment of the prostate lation of ERK phosphorylation depends on the
cancer cell line demonstrated the dependence of the MEK1 activity.
ERK nuclear localization on DNMT1, DNMT3a, The mechanism of such H2S-dependent effect on
DNMT3b mRNA and protein expression [38]. The ERK phosphorylation was later discovered by
studies on the colon cancer cell line demonstrated no K. Zhao and his colleagues. This research group
correlation between DNMT3a and DNMT3b ex- showed MEK1 sulfhydration at cysteine 341 in ex-
pression levels regarding ERK and MEK activity periments with the human endothelial cells, fibro-
and protein level, but showed such correlation for blasts and CSE knockout mice. In these experiments
the DNMT1activity and the protein level [39]. MEK1 sulfhydration induced ERK phosphorylation
Consequently, there is an evidence of strong de- and nucleus translocation [43].
pendence of DNMT1 expression on the Ras-ERK In the light of the above-mentioned mechanism of
signaling. Moreover, the mechanism of the DNMT1 DNMT1 transcription through AP-1 sites, H2S do-
transcription regulation by ERK-AP-1 pathway is nors and CBS or CSE inhibitors can affect MEK1
well described [29, 30, 38]. There are controversial sulfhydration and subsequent ERK activation and
data about [31, 32]. The data on DNMT3a and DNMT1 transcription. This field of research is open
DNMT3b transcription by the Ras-ERK signaling and may represent interest for further studies in mo-
are controversial, which gives room for further re- lecular biology.
search in the field.
Regulation of the Ras-ERK dependent DNMTs
H2S-dependent routes of the DNMTs transcription by redox activity of H2S
transcription regulation by the Ras-ERK Several studies demonstrate the role of oxidative
signaling stress and ROS in the regulation of general DNMTs
expression. For example, in vivo study demonstrates
Regulation of the Ras-ERK signaling-depen- DNMT1, DNMT3b, but not DNMT3a upregulation
dent DNMTs transcription by sulfhydration and subsequent DNA hypermathylation as a result of
H2S is a substrate of the cysteine residue sulfhydra- neonatal hypoxia [44]. S.O. Lim and his colleagues
tion reaction, PTM of proteins. There is a growing detected in vitro ROS dependent Snail protein over-
number of studies on the role of protein sulfhydra- expression, that regulates the HDAC1 and DNMT1
tion in the cell signaling [7]. Some of them are dedi- immobilization on gene promoters. In this experi-
cated to the Ras-ERK signaling dependence on the ment, the authors also identified the hypermethyl-
sulfhydration, the level of H2S concentration and the ation of E-cadherin gene promoter [45]. An interest-
activity of H2S producing enzymes [41–43]. It is ing study on the ROS regulation of the methylation
well-known that the ERK proteins dissociate from protein machinery localization was carried out with
binding partner MEK and undergo activation-based the human embryonal carcinoma cell line [46].
phosphorylation to perform their function [35]. A treatment of the cell culture with hydrogen perox-
There are in vitro experiments that show the H2S de- ide (H2O2) results in the increase of SIRT1 and
pendent ERK phosphorylation. For example, the DNMT1 chromatin binding force as well as the
treatment of mouse cardiomyocytes with H2S donor methylation protein complex consisting of DNMT1,
(NaHS) induces ERK phosphorylation, while inhibi- DNMT3B, SIRT1, EZH2 and γ-H2AX translocation
tion of the endogenous production of the gas has an to the transcriptional active genes, such as MYC,
opposite effect [41]. The identical treatment condi- ACTB, TIMP3 and MLH1. [47].H2O2 treatment in-
tions for the mouse embryonal cortical neuron cul- duced the catalase gene promoter hypermethylation
ture led to similar results [42]. Moreover, the authors and downregulation of the gene expression, as de-
use different inhibitors to show that the NaHS regu- scribed in the study using hepatocellular carcinoma

411
T. A. Nikitina

cell line. A pre-treatment with antioxidant, N-acetyl- The authors proved that H2S donors could regulate
cysteine, or DNMTs inhibitor 5-aza-deoxocytidine NADP+/NADPH balance and induce SOD2 expres-
prevented the effect of H2O2 on the gene promoter sion, after which DNMTs expression is down-regu-
methylation status and gene transcription [48]. lated [19].
Such sensitivity of DNMTs expression during Thus, as it was mentioned above, there are several
oxidative stress could be referred to as a result of a studies on the role of H2S in the regulation of DNMTs
well-known effect of oxidative stress on different expression and the Ras-ERK signaling during oxida-
cell signaling pathways, particularly the Ras-ERK tive stress. However, there are no direct studies on
signaling. Indeed, there are several PTMs of Ras and the role of H2S in the regulation of Ras-ERK-
Raf by ROS. Ras is oxidized on cysteine 118; Raf dependent DNMTs transcription in the oxidative
cysteine-rich domain is also oxidized by ROS. Such stress conditions. It is very important to explore or to
events result in the Raf membrane immobilization research the exact role H2S donors and inhibitors
and its subsequent activation [49–51]. There are also play in the regulation of Ras-ERK-dependent meth-
a few studies carried out with melanoma cell lines, ylation pattern under oxidative stress.
which demonstrate ROS induction of the Ras-ERK
dependent DNMT1 overexpression and DNA hyper- H2S regulation of the Ras-ERK signaling de-
methylation [52]. These data can prove our assump- pendent DNMTs transcription through NO
tion of an important role played by oxidative stress Nitric oxide (NO) is also an endogenously produced
and thereby antioxidants in the Ras-ERK dependent gas regulating cell signaling along with H2S. A rate-
DNMTs expression. limiting enzyme of NO biosynthesis is nitric oxide
There are a lot of studies on the role of antioxidant synthase (NOS) in humans. NO is a substrate of
properties of H2S, such as ROS scavenging, SOD2, protein nitrosylation and nitration. These PTMs are
eNOS induction, etc. [8, 13]. Consequently, we hy- important for the enzymatic function of proteins
pothesized that the ROS formation prevention by [53]. The results of a series of experiments showed
H2S could affect the Ras-ERK signaling and result in that H2S regulated the NOS expression and NO pro-
the methylation pattern modulation during oxidative duction [19, 13–16]. It was demonstrated that H2S
stress. Indeed, there are some studies on the role of donors up-regulated the endothelial NOS expres-
H2S in the Ras-ERK signaling regulation during oxi- sion and NO production by mouse aortic vascular
dative stress [17, 18]. For example, CoCl2 (the hy- smooth cells and the subsequent protein nitrosyl-
poxia mimetic) treatment of the myoblastic cell line ation in vivo [13]. GSNO, an NO carrier, releases
could stimulate ROS formation and subsequent ERK NO in the presence of H2S [14, 15]. The chemical
activation. A pre-treatment with H2S donor, NaHS, reaction of H2S with NO results in the formation of
and N-acetyl-l-cysteine could downregulate the ROS bioactive nitrosothiols, which release NO in the
level and ERK activity [17]. Similar experiments presence of Cu2+. H2S and nitrite produce HSNO in
with the pheochromocytoma cell line demonstrated the presence of endothelial cells or Fe3+-porphyrin.
the same results. The authors also discovered hy­po­ HSNO gene­rates NO or HNO by the subsequent re-
xia-inducible factor-1 alpha (HIF-1α) down-regu­la­ action with H2S [16]. Another study demonstrates
ted CBS expression. The pre-treatment with NaHS the inhibition of NOS and block of NO production
can compensate an effect of endogenous H2S and by endothelial cells of the mouse brain in vitro [11].
downregulate ERK activity in the oxidative stress Such property of H2S as NO induction could be im-
conditions [18]. There is also one study, which shows portant for the DNMTs expression regulation, be-
that down-regulation of DNMT1, DNMT3a, cause a number of studies highlighted the role of
DNMT3b expression levels after homocysteine NO in the regulation of DNA methylation. The first
treatment of endothelial cells was blocked by NaHS. data appeared during the research of Duchenne

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 The role of H2S in the DNMTs transcription regulation

The role of H2S in the cholesterol-dependent

regulation of the Ras-ERK signaling mediated
DNMTs transcription
Cholesterol is an important metabolite in humans at
both body and cell level. Consequently, not a sur-
prise that cholesterol metabolism affects epigenetics,
particularly DNA methylation pattern. It turned out
that several studies had proved the effect of meva­
lonate pathway inhibitors – statins – on DNMTs ex-
pression; however, they provide no evidence of a
direct role of the Ras-ERK signaling [62–64].
Fig. 2. Schematic representation of H2S-regulated PTMs of the The first study showed that the treatment of breast
Ras-ERK pathway enzymes (the author).
cancer, prostate cancer and osteosarcoma cells with
physiologically relevant concentrations of simvas-
muscular dystrophy. The authors identified NO- tatin induced down-regulation on DNMT1 expres-
dependent global DNA me­thy­lation [53]. The re- sion at the mRNA and protein levels [62]. The se­
search of the causes of gastritis demonstrated H. cond one showed that the lovastatin treatment of
Pylori bacteria infection stimulation of the macro- colorectal cancer cells reduced the DNMTs level and
phage NOS expression induced the NO-dependent BMP gene expression as a result of the gene pro-
DNA methylation in gastric mucosa [54, 55]. It is moter demethylation [63]. There is another study
known that the gene promoter methylation causes which demonstrated that the acute myeloid leukemia
the inhibition of transcription and there is evidence cells treatment with simvastatin had exerted a dose-
in the literature on the NO-dependent glo­bal gene dependent down-regulation effect on the DNMT1
silencing in endothelial cells [56]. and DNMT1 level [64].
Hypothesizing the regulation of Ras-ERK- The above-mentioned effect of cholesterol deple-
dependent DNMTs expression, we assume that ni- tion could be explained by the Ras-ERK signaling
trosylation of the Ras-ERK pathway enzymes could modulation by this molecule. It is well known, that
represent the NO-dependent mechanisms of DNA the plasms membrane (PM) structure is important
methylation regulation. Indeed, Cys118 of Ras and for cell signaling. PM contains the so-called “lipid
Cys 183 of ERK are S-nitrosylated [57, 58]; tran- rafts”, which are composed of cholesterol and
scriptional factor targets of the Ras-ERK signaling sphingolipids [65]. The lipid rafts harbor a lot of
pathways c-Fos and c-Jun (the elements of the AP-1 cell receptors and signaling proteins [66, 67]. The
transcriptional complex important for DNMTs Ras proteins belong to PM proteins, activated in
transcription) are also nitrosylated on cysteine resi- lipid rafts. It is discovered that a depletion of cho-
dues with subsequent block of AP-1 complex for- lesterol level in PM can block the Ras-ERK signa­
mation [59, 60]. On the other hand, NO could dem- ling [67]. The Ras proteins are also farnasylated at
onstrate an opposite effect on AP-1 complex ele- Cys-185 and Cys-186 by the products of mevalo­
ments stimulating c-Fos neurotrophin-dependent nate pathway of cholesterol biosynthesis, which is
expression [61]. done to achieve activity. At the same time, the block
In other words, the hypothesis of H2S-dependent of mevalonate pathway can inhibit the Ras-ERK
nitrosylation regulation of the Ras-ERK dependent signaling [68]. There is a need for additional studies
DNMTs transcription is supported by appropriate li­ to clarify a direct role of the Ras-ERK signaling
terature. However, this hypothesis requires additio­ modulation by cholesterol in the DNMTs transcrip-
nal scientific research to be proved completely. tion regulation.

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T. A. Nikitina

Fig. 3. Schematic representation of H2S-

mediated regulation of Ras proteins by
SREBP (the author).

All in all, what is a potential role of H2S in the DNMTs transcription through modulation of choles-
cholesterol-dependent Ras-ERK signaling mediated terol in a plasma membrane (PM). The second one is
the DNMTs expression? The recent data shed the the H2S-generated regulation of the Ras-ERK de-
light on the role of sulfhydration in cholesterol me- pendent DNMTs transcription through the modula-
tabolism regulation. It is known that Sterol regulatory tion of protein prenylation.
element-binging protein (SREBP) is a transcription
factor which induces the transcription of cholesterol Conclusions
biosynthesis genes [69]. There are several stu­dies The review presents the data which support our hy-
which show that H2S stimulates the cholesterol bio- pothesis about H2S regulation of the Ras-ERK sig-
synthesis through SREBP regulation [9–11]. For ex- naling dependent DNMTs transcription. The relevant
ample, a treatment of pancreas beta-cells with H2S literature showed a series of experiments, whereby
donors, or the transfection with constitutional active both H2S exogenous donors and endogenous gas
cse gene induced up-regulation of (SREBP)-1c [9]. could affect PTMs of Ras, Raf, MEK1 and ERK pro-
An adipocytes maturation is accompanied by the H2S teins. H2S can regulate sulfhydration, oxidation, ni-
biosynthesis genes overexpression. Moreover, this trosylation and prenylation thereby modulating the
study indicates the main role of H2S in lipoge­nesis Ras-ERK signaling dependent and independent
[10]. It describes a CBS-dependent translocation of DNMTs expression in vitro and in vivo. We believe
Sp1 to the nucleus and the SREBP gene promoter our hypothesis can be the basis for developing new
binding in the experiments with the ovarian cancer drugs or transforming the existing treatment strate-
cells [11]. The research of the H2S dependent mecha- gies for different diseases associated with the DNA
nism of SREBP regulation results in the discovery of methylation disorders. There is a need for further
Sp1 sulfhydration at Cys68 and Cys755 [12]. studies to elucidate the detailed mechanisms of H2S
Furthermore, the authors proved that such PTM is a impact on the Ras-ERK signaling dependent DNMTs
driving force for SREBP up-regulation and subse- transcription.
quent lipogenesis through the regulation of Sp1 nu-
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