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Free Radical Biology and Medicine 87 (2015) 84–97
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Free Radical Biology and Medicine
journal homepage: www.elsevier.com/locate/freeradbiomed
Regulation of catalase expression in healthy and cancerous cells
Christophe Glorieux a, Marcel Zamocky b,c, Juan Marcelo Sandoval a, Julien Verrax a,
Pedro Buc Calderon a,d,n
a
Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université catholique de Louvain, 1200 Brussels, Belgium
Division of Biochemistry, Department of Chemistry, University of Natural Resources and Life Sciences (BOKU), A-1190 Vienna, Austria
c
Institute of Molecular Biology, Slovak Academy of Sciences, SK-84551 Bratislava, Slovakia
d
Facultad de Ciencias de la Salud, Universidad Arturo Prat, 1100000 Iquique, Chile
b
art ic l e i nf o
a b s t r a c t
Article history:
Received 16 March 2015
Received in revised form
8 June 2015
Accepted 10 June 2015
Available online 25 June 2015
Catalase is an important antioxidant enzyme that dismutates hydrogen peroxide into water and molecular oxygen. The catalase gene has all the characteristics of a housekeeping gene (no TATA box, no
initiator element sequence, high GC content in promoter) and a core promoter that is highly conserved
among species. We demonstrate in this review that within this core promoter, the presence of DNA
binding sites for transcription factors, such as NF-Y and Sp1, plays an essential role in the positive regulation of catalase expression. Additional transcription factors, such as FoxO3a, are also involved in this
regulatory process. There is strong evidence that the protein Akt/PKB in the PI3K signaling pathway plays
a major role in the expression of catalase by modulating the activity of FoxO3a. Over the past decade,
other transcription factors (PPARγ, Oct-1, etc.), as well as genetic, epigenetic, and posttranscriptional
processes, have emerged as crucial contributors to the regulation of catalase expression. Altered expression levels of catalase have been reported in cancer tissues compared to their normal counterparts.
Deciphering the molecular mechanisms that regulate catalase expression could, therefore, be of crucial
importance for the future development of pro-oxidant cancer chemotherapy.
& 2015 Published by Elsevier Inc.
Keywords:
Catalase
Transcription regulation
Cancer
Transcription factors
Catalase promoter
Free radicals
Contents
1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
1.1.
Generalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
1.2.
Catalase expression and activity in rodents and humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
1.3.
Role of catalase in healthy and cancerous cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Transcriptional regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.1.
Sp1 and CCAAT-binding proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
2.2.
FoxO transcription factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
2.2.1.
FoxO3a transcription factor and its regulation by the PI3K/Akt signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
2.2.2.
FoxO3a and coactivators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
2.2.3.
Other Forkhead box transcription factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
2.3.
Peroxisome proliferator-activated receptor γ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
2.4.
Other transcription factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
2.5.
Humoral factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Abbreviations: Abl, Abelson murine leukemia viral oncogene homolog 1; Akt/PKB, protein kinase B; bZIP, basic leucine zipper; C/EBP-β, CCAAT-enhancer-binding protein β;
Egr, early growth response; ER, estrogen receptor; Fox, Forkhead box protein; hGH, human growth hormone; HNRF, hepatocarcinogenesis-related negative-regulatory factor;
JunB, JunB proto-oncogene; MAPK, mitogen-activated protein kinase; MEF, mouse embryonic fibroblast; mTOR, mammalian target of rapamycin; NF-Y, nuclear factor Y; Nrf2,
nuclear factor (erythroid-derived 2)-like 2; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; PI3K, phosphoinositide 3-kinase; POU2F1 (Oct-1), POU
domain class 2 transcription factor 1; PPARγ, peroxisome proliferator-activated receptor γ; PPRE, PPAR-response element; PTEN, phosphatase and tensin homolog; ROS,
reactive oxygen species; Sirt1, Sirtuin 1; SOD, superoxide dismutase; Sp1, specificity protein 1; SV40, simian virus 40; UTR, untranslated region; WT1, Wilms tumor 1; XBP1,
X-box binding protein 1
n
Corresponding author.
E-mail address: [email protected] (P.B. Calderon).
http://dx.doi.org/10.1016/j.freeradbiomed.2015.06.017
0891-5849/& 2015 Published by Elsevier Inc.
C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
3.
Other processes regulating catalase expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Genetic alterations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Epigenetic regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Posttranscriptional and posttranslational regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Developing strategies to modulate catalase protein levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
1.1. Generalities
The human catalase gene is located on the short arm of chromosome 11 [1] and has all the characteristics of a housekeeping
gene, with no TATA box, no initiator element sequence, and high GC
content in the promoter [2]. The complete genomic DNA coding
sequence for catalase has 32,420 bp and contains 12 introns and 13
exons, generating an mRNA of 2287 bp [2] encoding a single protein
of 526 amino acids. The enzyme (EC 1.11.1.6), first described by
Loew more than 100 years ago [3], is a homotetramer in which each
monomer (62.5 kDa) contains a heme b group responsible for the
enzymatic activity [4]. The human catalase belongs to the family of
typical catalases [5], which predominantly catalyze the dismutation
of hydrogen peroxide (H2O2) into water and molecular oxygen. In
addition to its dominant “catalatic” activity (decomposition of
H2O2), catalase can also decompose peroxynitrite [6–8], oxidize
nitric oxide to nitrogen dioxide [9], and exhibit marginal peroxidase
(i.e., oxidation of organic substrates with concomitant reduction of a
peroxide ) [10] as well as low oxidase activity (O2-dependent oxidation of organic substrates) [11].
In metazoans, catalase is expressed in all major body organs,
especially in the liver, kidney, and erythrocytes [12, 13], where it
plays an essential role in cell defense against oxidative stress [14].
The enzyme is mainly located in peroxisomes [15, 16], but a
functional catalase has also been detected in the cytoplasm [17,
18], in the mitochondria of rat cardiomyocytes [19], and on the
cytoplasmic membrane of human cancer cells [20].
1.2. Catalase expression and activity in rodents and humans
Altered catalase expression has been associated with several diseases. For example, certain polymorphisms in the catalase gene have
been described in diabetes, hypertension, vitiligo, Alzheimer disease,
and acatalasemia, leading to decreased catalase activities [21, 22].
Catalase is frequently downregulated in human and rodent tumor tissues compared to normal tissues of the same origin [23–35].
The low levels of catalase expression correlate with a high production of H2O2, which is involved in the activation of signaling
pathways to induce proliferation, migration, and invasion in cancer
cells [36–38]. We have previously reported an important decrease
in catalase activity in both human and murine cancer cells [39, 40].
These observations are consistent with a study by Sun et al., who
showed that immortalization and transformation of mouse liver
cells with SV40 (simian virus 40) resulted in a decrease in catalase
expression that contributed to oncogenesis by increasing reactive
oxygen species (ROS) levels in transformed cells [41].
Conversely, catalase levels increase in rat hepatocytes and astrocytes as well as in Chinese hamster V79 fibroblasts after shortduration exposure to H2O2 [42–44]. However, short-term exposures
to oxidants (i.e., hydrogen peroxide, menadione, tert-butyl hydroperoxide) fail to induce catalase protein levels in MCF-7 breast
cancer cells, MRC-9 normal lung fibroblasts, or PC12 rat pheochromocytoma cells [45–47]. The expression of other H2O2-
85
92
92
93
93
93
94
94
degrading enzymes (i.e., glutathione peroxidase) is induced and
may counteract the increased ROS level in MCF-7 after exposure to
oxidants [45]. It is noticed that the change in catalase expression,
after short-term H2O2 exposure, would be influenced by several
factors: the exposure time, the H2O2 concentration, the basal antioxidant enzyme capacity of the cells, and the cellular model used.
Moreover, in patients suffering from mesothelioma and in rat
glioma cells, catalase protein levels are increased, conferring cellular protection against epirubicin and ionizing radiation (137Cs γrays), respectively [48, 49]. Increased catalase expression has been
observed in tumors from patients with gastric carcinoma, skin
cancer, and chronic myeloid leukemia [50–53] and in human HL60 cancer cells rendered resistant to chronic exposure to H2O2
[54–56]. This high catalase expression has also been observed in
several human cancer cell lines (e.g., gastric, oral, pancreatic,
bladder) exposed to cisplatin [57], ascorbic acid [58], bleomycin
[59], gemcitabine [60], mitomycin C [61], hormonal therapy [62],
and ionizing radiation [63].
1.3. Role of catalase in healthy and cancerous cells
The importance of catalase for human life is illustrated by the
diseases that are associated with mutations of its gene. For example, acatalasemia is an autosomally inherited deficiency of erythrocyte catalase due to guanine-to-adenine substitution (Japanese type A), threonine deletion (Japanese type B), or guanine–
adenine insertion (Hungarian type) [64–66]. Acatalasemia is
characterized by a specific catalatic activity of less than 5% compared to normal rates; it is still rare and usually benign but can
sometimes be problematic, resulting in oral gangrene ulceration
for Japanese patients or in essential hypertension [67–69]. Catalase
polymorphism has also been associated with the occurrence of
diabetes, vitiligo, or Alzheimer disease [21, 22]. Regarding catalase
downregulation, it should be noted that catalase-deficient mice
are viable and fertile [70]. They develop normally with a normal
hematological profile, but after trauma the mitochondria show
defects in oxidative phosphorylation. This phenotype could be
explained by the presence of other H2O2-degrading enzymes such
as glutathione peroxidases and peroxiredoxins. On the other hand,
the enzyme was also overexpressed in mice. Mitochondrial catalase overexpression in mice enables a life-span increase of 20%
[71]. In these mice, the mitochondrial deletions are reduced; they
prevent heart disease and the onset of cataracts.
As previously cited, the first function assigned to catalase is the
transformation of hydrogen peroxide into oxygen and water (2
H2O2 - 2 H2O þ O2). It thus plays an important role in defending
cells against oxidative damage by degrading hydrogen peroxide.
However, increasing evidence suggests that catalase is also involved in various other processes.
Indeed, ROS are able to activate various signaling pathways, such
as that of mitogen-activated protein kinase (MAPK) to increase the
capacity for proliferation, migration, and invasion [38]. Catalase can
modulate the growth rate by various mechanisms, the first obviously being its ability to detoxify H2O2. The second is its ability to
bind and protect certain proteins from potential oxidative damage,
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C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
such as Grb2 and SHP2, involved in integrin pathways, which in
turn are themselves involved in the processes of proliferation and
migration [72, 73]. As shown by many reports, catalase and mitochondrial superoxide dismutase control cell growth and migration processes in cancer cells [74–77].
Surprisingly, when exposed to UVB rays, catalase can also
produce ROS via NADH oxidation [78]. In addition, overexpression
of catalase protects cells against DNA damage induced by UVB and
X-rays [79, 80].
Catalase, as catalase-peroxidase, also possesses oxidase activity
[11]. The oxidase activity requires oxygen in addition to electron
donors as it is heme-dependent. Phenols (benzene derivatives),
alcohols, aryl amines, and other carcinogens are substrates and/or
inhibitors of oxidase function. Certain metabolites, when metabolized by catalase, are active as indole and the neurotransmitter
β-phenethylamine [11]. Thus, catalase may also have additional
roles such as the detoxification or activation of toxic and anti-tumor compounds. We have explored a potential role of catalase
during the acquisition of cancer cell resistance to chemotherapeutic agents. To this end, we overexpressed human catalase in
MCF-7 cells, a human-derived breast cancer cell line. No particular
resistance against conventional chemotherapies such as doxorubicin, cisplatin, or paclitaxel was observed in cells overexpressing
catalase, but cells were more resistant to the pro-oxidant combination ascorbate and menadione [74]. This association generates a
redox cycling that induces ROS production (mainly H2O2) and
exhibits a strong preferential ability to kill cancer cells [39, 40, 74].
Tumor cells frequently produce large amounts of reactive
oxygen species [81]. This can be explained by the presence of
mitochondrial defects and a decreased expression of antioxidant
enzymes such as catalase or manganese superoxide dismutase [82,
83]. Instead of the phenotype observed in catalase-knockout mice
and acatalasemic patients, the expression of other antioxidant
enzymes is also altered in cancer cells [83]. ROS play an important
role in tumorigenesis and tumor progression by inducing DNA
mutations and genomic instability. On the other hand, high levels
of ROS can induce cell death and alterations in redox regulation
and redox signaling conducted for the development of potential
anti-cancer therapies [84–87].
The structure, the mechanism of enzyme activity, and the phylogeny of catalase have already been extensively reviewed [5, 88–92].
However, the molecular mechanisms controlling catalase expression
are still poorly understood, as are those explaining the altered expression of catalase in cancer cells. Therefore, the aim of the following
sections is to review current knowledge regarding the various mechanisms known to regulate catalase expression. To this end, the
critical roles played by Sp1 (specificity protein 1), NF-Y (nuclear factor
Y), FoxO (Forkhead box protein O), and other transcription factors
such C/EBP-β (CCAAT-enhancer-binding protein β), PPARγ (peroxisome proliferator-activated receptor γ), and Oct-1 (POU2F1), as well
as the pathways regulating their activities in normal and cancer cells,
will be considered. Regulation at other levels, including genetic, epigenetic, and posttranscriptional modifications, will also be discussed.
2. Transcriptional regulation
The human catalase gene was first described in 1986 [2]; rat
and mouse catalase genes were isolated and characterized in the
next decade [93, 94]. Catalase expression is predominantly regulated at the level of transcription by transcription factors that induce or repress the transcriptional activity of human and rodent
catalase promoters. Fig. 1 shows these transcription factors, specifying both the species and the exact position of the binding sites
as obtained from the literature. Moreover, the bioinformatics
analysis of catalase promoters among different species shows the
presence of a major regulatory region in which Sp1, NF-Y, and C/
EBP-β DNA binding induces activation of catalase gene transcription (Figs. 1 and 2).
2.1. Sp1 and CCAAT-binding proteins
The catalase core promoters, located approximately in the first
200 bp of the upstream region of the catalase promoters, are rich
in GC residues and contain both GGGCGG and CCAAT boxes
(Fig. 2). As previously mentioned, transcription factors, such as Sp1
and NF-Y, which respectively bind to these two boxes, regulate the
transcription of several genes and the subsequent expression of
proteins, including human α1(I) collagen [95], α7-nicotinic receptor [96], human γ-globin [97], and homeobox B4 [98]. Moreover, given the capacity of Sp1 to recruit RNA polymerase II [99],
Sp1 is of critical importance to drive the transcription of TATA-less
gene promoters, such as human glypican 3 [99], lens epitheliumderived growth factor/p75 [100], and survivin [101]. Because of the
characteristics of the catalase core promoter, it has been hypothesized that these two transcription factors (Sp1 and NF-Y)
may have a role in the positive regulation of catalase expression.
A nice mechanistic study conducted by Nenoi et al. showed that
these factors regulate the expression of catalase in cancer cells [55].
Indeed, compared to the parental cell line, increased expression of
catalase was observed in HP100 human leukemia cells (derived
from HL-60 cells rendered resistant to H2O2). This phenotype was
associated with high nuclear levels of both Sp1 and NF-Y, which
bind, respectively, to the GGGCGG box located 70 bp and to the
CCAAT element located 92 bp (Fig. 2) [55] from the start transcription site (þ1) defined by Yoo et al. [102]. In the same study, the
authors showed that Sp1 activity, and as a consequence the expression of catalase, may be downregulated by its interaction with
another transcription factor related to a member of the Egr (early
growth response) protein family under specific circumstances. Indeed, HP100 cells exposed to an ROS-generating system (X-rays)
showed lower catalase activities compared to unexposed cells [55].
The explanation proposed by these authors was the induction of an
Egr-related factor, competing with an overlapping Sp1/Egr1 recognition sequence located within the core promoter of the catalase
gene [55]. Indeed, both transcription factors, namely Sp1 and Egr1,
have opposite transactivating effects when they share an overlapped sequence. Therefore, this association may lead to promoter
impairment by disturbing or competing with the transactivating
ability of Sp1 [103]. A similar effect of WT1 (Wilms tumor 1) on Sp1
activity was observed in a multistep chemical carcinogenesis mouse
model. The induction of cell carcinoma led to increased expression
of WT1, which binds to the GC box, probably reducing the binding
of Sp1 to the same element, and leading to the loss of catalase
promoter transactivation (Figs. 1 and 2) [29].
NF-Y positively regulates catalase expression by binding the
CCAAT box in the mouse core promoter (Figs. 1 and 2) [94, 104].
The NF-Y binding and the subsequent catalase transcription are
enhanced by X-box binding protein 1 (XBP1) via an unknown
mechanism interfering with the NF-Y/catalase promoter complex
formation [105]. XBP1 is a major endoplasmic reticulum stresslinked transcriptional factor that belongs to the basic region/leucine zipper (bZIP) family and is activated on accumulation of unfolded protein [106]. In this context, decreased catalase expression
associated with increased sensitivity to H2O2 was observed in
XBP1-deficient MEFs (mouse embryonic fibroblasts) compared to
wild-type cells [105]. Interestingly, this phenotype was reversed
by XBP1 overexpression [105]. Because the human catalase promoter also contains NF-Y DNA binding sites (Figs. 1 and 2) [55], it is
expected that XBP1 may regulate NF-Y binding activity, thus affecting human catalase expression. Indeed, genetic manipulation,
for example, knockdown of XBP1 by small interfering RNA (siRNA),
C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
87
Fig. 1. Transcription factor binding sites in human, mouse, and rat catalase promoters. Because authors labelled different transcription start sites in their publications, the
positions of the transcription binding sites in this table were all defined from the ATG translation start ( þ1). Abbreviations: FoxM1, Forkhead box protein M1; Oct-1/POU2F1,
POUdomain class 2 transcription factor 1; PPARγ, peroxisome proliferator-activated receptor γ; NF-Y, nuclear factor Y; Sp1, specificityprotein1; C/EBP-β, CCAAT-enhancerbinding protein β; FoxO1, Forkhead box protein O; HNRF, hepatocarcinogenesis-related negative regulatoryfactor; and WT1, Wilms tumor 1.
resulted in reduced expression of catalase and superoxide dismutase genes in both human retinal pigment epithelium [107] and
glioma cell lines [108].
In addition to Sp1 and NF-Y, C/EBP-β, a member of the bZIP family of transcription factors implicated in gene regulation of immune and inflammatory responses [109], is another factor involved
in the transcriptional activation of the catalase gene in rats
(Figs. 1 and 2). Taniguchi et al. showed that a C/EBP-β binding element on the rat catalase promoter was critical for transcription
from multiple initiation sites and that C/EBP-β actually binds to this
site, regulating gene transcription in the catalase promoter [110].
In addition to GGGCGG and CCAAT boxes, analysis of the promoter region in the rat catalase gene reveals a pair of invertedrepeat motifs located at the 54/ 41 and 104/ 91 positions
(before the first ATG codon). Such motifs have also been identified
in human and mouse catalase promoters, and the core sequence of
this element is GYCMGGCCCKCTCYKG, where Y ¼ T or C, M ¼ A or
C, and K ¼ G or T [111]. Functional analysis of this promoter region, performed on the first motif, revealed that four different and
still undetermined proteins were observed to bind to this sequence, affecting catalase gene expression [111]. Interestingly, the
region surrounding the former inverted-repeat region ( 72/ 26)
seems to hold basic promoter activity and includes the C/EBP-β
binding site mentioned before ( 45/ 34) [111].
Because the first 200 bp of the upstream region of the catalase
promoter is the best characterized and is well conserved in humans and rodents, the search for homologous sequence regions in
genomes of related vertebrates was explored. Fig. 2 presents
highly conserved regions that were detected in the multiple sequence alignment of 15 phylogenetically related sequences of
genomic segments of the catalase promoter regions from selected
vertebrate genomes. Although the transcription start site, known
from the human catalase promoter [102], is not perfectly conserved among all presented sequences (Fig. 2), a high level of
conservation may be observed mainly in regions identified as
binding sites for various transcription factors that have already
been mentioned. It is interesting to see that in the upper part of
this DNA alignment, the motif CCAAT occurs twice in close
proximity. However, for effective binding of NF-Y, the embedding
motifs are also essential, as already shown in humans and mice
(Figs. 1 and 2). Hence, only the posterior region labeled with asterisks in Fig. 2 is capable of NF-Y binding, and the preceding motif
labeled with solid circles may be just the product of a short duplication event with as yet unknown binding capability for transcription factors. The next conserved region responsible for Sp1/
Egr/WT1 binding (Fig. 2, upper right) is highly conserved among
primates. Interestingly, there is a short insertion in the gibbon
sequence and a long insertion in the rhesus sequence that can
influence the binding of these transcription factors. For rodents
and for the fish sequence there are deletions at the same place, so
the real binding of Sp1/Egr/WT1 in all these organisms has to be
verified experimentally. For the C/EBP-β transcription factor (Fig. 2,
lower part), a longer insertion can be observed in the fish sequence and a slight modification with a short insertion in the
rodent sequence. Again, this sequence motif is highly conserved
among primates, indicating strong binding ability. Thus, it may be
concluded that a rather high degree of sequence conservation in
the presented region only among mammals reveals that a multiple transcriptional regulation within the catalase promoter was
developed during an extensive evolution to high complexity
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Fig. 2. Multiple sequence alignment of the upstream promoter region of 15 selected catalase genes. Multiple sequence alignment was performed with MUSCLE software (R.C.
Edgar, Mill Valley, CA, USA) taking the upstream promoter region of 15 selected catalase genes including sequences from primates, nonprimate mammals, rodents, and
zebrafish. Color scheme: blue, 485% sequence identity; green, 50–85%; yellow, 25–50%; and white, o 25%. The consensus sequence is obtained from the most frequent
nucleotide residue found at each position. Important regions, discussed in the text, are highlighted with asterisks. A conserved CCAAT region is also noted with closed circles.
GenBank accession numbers: Homo sapiens (human), NG_013339.1; Pongo abelii (orangutan), NW_002885194.1; Pan troglodytes (chimpanzee), NW_003457670.1; Pan paniscus (pygmy chimpanzee), NW_003870611.1; Gorilla gorilla (gorilla), CABD02060366.1; Nomascus leucogenys (white-cheeked gibbon), NW_003501373.1; Macaca mulatta
(rhesus macaque), NW_001100376.1; Callithrix jacchus (common marmoset), NW_003184090.1; Otolemur garnettii (greater galago), NW_003852396.1; Rattus norvegicus
(brown rat), AC_000071.1; Mus musculus (house mouse), NT_039207.8; Bos taurus (cattle), NW_003104419.1; Sus scrofa (wild boar), CU582930.10; Canis familiaris (dog),
NC_006596.3); and Danio rerio (zebrafish), NW_003336217.1. Abbreviations: NF-Y, nuclear factor Y; Sp1, specificity protein 1; WT1, Wilms tumor 1; Egr, early growth
response; C/EBP-β, CCAAT-enhancer-binding protein β; and ORF, open reading frame.
within mammalian genomes and remains to be compared with
the regulation of other antioxidant enzymes in various vertebrates.
Table 1 summarizes additional transcription factors, coactivators, and/or signaling pathways that have been involved either as
activators or as repressors controlling catalase gene expression.
They will be discussed in the next sections.
2.2. FoxO transcription factors
The FoxO family consists of four proteins (FoxO1, 3a, 4, and 6)
that regulate hormonal, nutrient, and stress responses. They share
marked similarity in structure, function, and regulation in mammalian organisms [112]. Regulation of the FoxO protein family is
posttranslationally controlled by the Akt/PKB signaling pathway
[113, 114]. Indeed, the serine/threonine kinase, Akt, phosphorylates FoxO, which is consequently excluded from the nucleus by
14-3-3 protein and degraded by the ubiquitin proteasome system
[113, 114].
In this context, FoxO3a and other Forkhead box family members such FoxO1 and FoxM1 (Forkhead box protein M1) have been
mentioned as positive regulators of catalase expression (Fig. 1 and
Table 1).
C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
Table 1
Activators and repressors involved in transcriptional regulation of the catalase gene
Transcription factor/
coactivator/signaling
pathway
Cell/tumor type
Transcriptional activators that control catalase gene expression
Sp1
Human HL-60 and HP100 promyelocytic
leukemia cell lines
NF-Y
Human HL-60 and HP100 promyelocytic
leukemia cell lines
Rat liver cells
Mouse muscle cells
XBP1 and NF-Y
Human HeLa cervical cancer cell line
Human retinal pigment epithelial cells
Human glioma cell lines
Mouse embryonic fibroblasts
C/EBP-β
Rat Reuber hepatoma cell line
FoxO3a
Rat cardiomyocytes
Rat vascular smooth muscle cells
Mouse embryonic fibroblasts
FoxO3a, PGC-1α, and Sirt1 Human HeLa cervical cancer cell line
Rat PC12 pheochromocytoma cells
Mouse embryonic fibroblasts
Sirt1 mediated
Human proximal tubular cell lines
Rat heart and adipose tissues
FoxM1
Human primary fibroblasts and U2OS osteosarcoma cells
Mouse embryonic fibroblasts
FoxO1
Rat vascular smooth muscle cells
Rat glomerular mesangial cells
PPARγ
Human differentiated primary adipocytes
Human melanocytes
Rat brain microvascular endothelial cells
Rat oligodendrocytes
Rat cardiomyocytes
Rat astrocytes
Rat fibroblasts
Mouse neuronal cells
Mouse adipocytes
Oct-1
Human hepatocellular carcinoma cell lines
Nrf2
Mouse cardiac fibroblasts
Mouse macrophages
Mouse myocardiac cells
PR
Human breast cancer cells and normal
epithelial breast cells
MAPK signaling
Human MCF-7 breast cancer cell line
Transcriptional repressors that control catalase gene expression
WT1/Egr-related factor
Human HL-60 and HP100 promyelocytic
leukemia cell lines
WT1
Mouse benign papilloma and malignant
carcinoma (cells and tissues)
HNRF
Rat hepatoma cells
ER
Human breast cancer cell lines
PI3K/Akt/mTOR (signaling Human MCF-7 breast cancer cell line
pathways)
Human non-small-cell lung cancer cell lines
Human HepG2 hepatoma cell line
Human airway smooth muscle from asthmatic and chronic obstructive pulmonary
disease patients
Rat vascular smooth muscle cells
Ref.
[55]
[55]
[93]
[104]
[105]
[107]
[108]
[105]
[110]
[118]
[119]
[127]
[130]
[130]
[129]
[132]
[131]
[133]
[133]
[134]
[135]
[139]
[147]
[140]
[142]
[143]
[144]
[145]
[146]
[141]
[155]
[157]
[158]
[159]
[172]
[170]
[55]
[29]
[166]
[171]
[120]
[123]
[124]
[173]
[119]
Abbreviations: FoxM1, Forkhead box protein M1; Oct-1/POU2F1, POUdomain class
2 transcription factor 1; PPARγ, peroxisome proliferator-activated receptor γ; NF-Y,
nuclear factor Y; Sp1, specificityprotein1; C/EBP-β, CCAAT-enhancer-binding protein
β; FoxO, Forkhead box protein O; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; HNRF, hepatocarcinogenesis-related negative regulatoryfactor; WT1, Wilms tumor 1; XBP1, X-box binding protein 1; Sirt1, Sirtuin 1; Nrf2,
nuclear factor (erythroid-derived 2)-like 2; PR, progesterone receptor; MAPK, mitogen-activated protein kinase; hGH, human growth hormone; Egr, early growth
response; ER, estrogen receptor; PI3K, phosphoinositide 3-kinase; Akt/PKB, protein
kinase B; mTOR, mammalian target of rapamycin).
2.2.1. FoxO3a transcription factor and its regulation by the PI3K/Akt
signaling pathway
Among many other target genes, FoxO3a transcription factor
regulates the expression of antioxidant enzymes, such as catalase and
89
mitochondrial superoxide dismutase, mainly in rodents [115–117].
In rats, FoxO3a positively regulates catalase expression by
binding to the ATAAATA sequence in its promoter (Fig. 1) [118].
Consequently, silencing FoxO3a leads to a reduction in the levels of
catalase mRNA and protein in isolated rat cardiomyocytes [118]
and in catalase protein levels in rat vascular smooth muscle cells
[119]. Nevertheless, in MCF-7 cells (a human breast cancer cell
line), modulating FoxO3a expression by using either knockdown
or overexpression strategies did not change the expression of
catalase [120]. Although putative FoxO3a binding sites have not
been identified in the human catalase gene, the involvement of
other Forkhead box family members cannot be excluded (i.e.,
FoxO1, FoxO4). In fact, these transcription factors share high similarity in their structure, function, and regulation [112] and
maybe counteract the loss of FoxO3a in cells.
Increased catalase expression was observed when rat vascular
smooth muscle [119] and human MCF-7 cancer cells [120] were
incubated in the presence of LY294002, a well-known PI3K
(phosphoinositide 3-kinase) inhibitor, provoking inhibition of the
PI3K/Akt signaling pathway. Given that FoxO3a activity is repressed after its phosphorylation by Akt kinase [121], inhibition of
the PI3K/Akt pathway hinders the phosphorylation of FoxO3a and
prevents its translocation out of the nucleus. Because LY294002
can also inhibit the kinase mTOR (mammalian target of rapamycin) [122], the effect of rapamycin (an mTOR inhibitor) has also
been studied. As with LY294002, rapamycin increased the expression of catalase in MCF-7 cells [120].
In human non-small-cell lung cancer cell lines, the protein
phosphatase PTEN (phosphatase and tensin homolog) inhibits the
PI3K/Akt pathway and, most likely by this method, increases the
protein levels of catalase and other antioxidant enzymes, such as
superoxide dismutase and glutathione peroxidase [123]. Conversely, activation of the PI3K/Akt pathway by arsenite treatment
of HepG2 (human hepatoma) cells led to a decrease in catalase
protein levels [124].
These results suggest that, in human cancer cells, downregulation
of catalase is dependent on PI3K/Akt/mTOR, most likely via a putative
unknown nuclear repressor, whereas FoxO3a does not play a critical
role. Indeed, experimental evidence showing that FoxO3a regulates
the expression of catalase has been mainly observed in mouse and
rat cells (Fig. 1 and Table 1). However, in human breast MCF-7 cells,
modulation of FoxO3a, either by enhancing or by decreasing its levels, did not affect the expression of catalase [120].
2.2.2. FoxO3a and coactivators
The need for some coactivators during catalase expression by
FoxO3a has also been evoked. Indeed, the FoxO3a transcription factor
cooperates with the transcriptional coactivator peroxisome proliferator¼ activated receptor γ coactivator 1α (PGC-1α) and the histone
deacetylase Sirt1 (Sirtuin 1), to regulate the expression of catalase.
PGC-1α is a positive regulator of mitochondrial function and
oxidative metabolism [125] and has been involved in the regulation of gene transcription implicated in ROS detoxification [126].
When MEF cells were made double knockout (KO) for FoxO3a and
PGC-1α, they displayed decreased levels of antioxidant enzymes
(catalase, superoxide dismutase, and some peroxiredoxins) [127].
Interestingly, the overexpression of FoxO3a in MEF cells with only
PGC-1α knocked out did not modify catalase expression, suggesting that FoxO3a requires the presence of PGC-1α to induce catalase
expression [127].
Sirt1 is also involved in FoxO transcriptional activity and, most
likely, in catalase expression. Sirt1 belongs to a family of NAD
(þ)-dependent protein-modifying enzymes with activities in lysine deacetylation and is involved in the regulation of gene expression, DNA damage repair, metabolism, and survival [128]. Both
FoxO3a and PGC-1α are activated by Sirt1-mediated deacetylation,
90
C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
thereby increasing the formation of FoxO3a/PGC-1α complexes
and modulating the expression of catalase and other antioxidant
enzymes in normal and cancer cell lines [129, 130].
In support of this model of a cooperative regulatory process,
when Sirt1 activity was stimulated in heart and adipose tissues by
exercise training in rats, increased levels of both FoxO3a and catalase
were observed [131]. Furthermore, the use of Sirt1 inhibitors decreased catalase expression, whereas their overexpression increased
catalase expression in human proximal tubular cell lines [132].
either by cytosolic molecules that interfere with signaling or related to a direct effect of PPAR agonists/antagonists [151]. Finally,
PPARγ-mediated transcriptional activation of its target genes is a
plausible explanation for PI3K/Akt signaling regulation. A clear
example is the activation of the tumor suppressor PTEN. This
protein dephosphorylates inositol phospholipid intermediates of
the PI3K pathway, inhibiting activation of downstream targets,
such as Akt, in both normal and cancer cells [152, 153].
2.4. Other transcription factors
2.2.3. Other Forkhead box transcription factors
The transcription factor FoxM1 has been shown to positively
modulate catalase expression and the FoxM1 binding sequence
was identified as TGTTTGTT in the first intron (Fig. 1). FoxM1 has
critical functions in tumor development and progression. Indeed,
it is induced by the oncogene Ras and is essential for the regulation of ROS levels in primary human fibroblasts [133].
Another member of the Forkhead transcription factor family,
FoxO1, cooperates with PGC-1α to bind the rat catalase promoter
at the consensus sequence TTATTTAC (Fig. 1) [134]. The suppression of PGC-1α activity due to covalent modifications caused by
the protein kinase Akt or the histone acetyltransferase general
control nonderepressible 5 (Gcn5) prevents DNA binding of FoxO1
to the catalase promoter and represses the expression of the enzyme [134]. Moreover, overexpressing an active form of FoxO1
stimulated the levels of catalase protein in rat glomerular mesangial cells [135]. To our knowledge, no data have been reported
about a putative role of FoxO1 on catalase expression in cancer
cells.
2.3. Peroxisome proliferator-activated receptor γ
An additional well-known activator of the transcription of the
catalase gene is PPARγ. The family of PPARs contains three members (PPARα, β/δ, and γ) and plays an essential role in the regulation of development and lipid metabolism [136, 137]. PPARs
mostly form heterodimers with retinoid X receptor before binding
to the PPRE (PPAR-response element) of their target genes [138].
Fig. 1 shows that PPARγ binds to a PPRE sequence TGACCTTTGCAAA in the human catalase promoter and subsequently induces
catalase gene transcription [139].
Other PPRE sequences have been reported in rodent catalase
promoters [140, 141] (Fig. 1), and increased catalase expression
mediated by PPARγ agonists (e.g., pioglitazone) has been observed
in rat oligodendrocytes, cardiomyocytes, fibroblasts, and astrocytes [142–145]. Moreover, neurons from PPARγ mutant mice
showed a decrease in the expression of catalase and other antioxidant enzymes, such as superoxide dismutase and glutathione Stransferase; impaired expression of prosurvival genes; and greater
damage as a result of oxidative stress [146]. Silencing PPARγ in
human melanocytes also decreased catalase expression, whereas
cell exposure to 2,4,6-octatrienoic acid (a PPARγ activator) led to
increased levels of catalase in these cells [147]. Recently, inhibition
of PPARγ transcription activity by the Parkinson disease-related
protein α-synuclein led to decreased levels of catalase mRNA,
protein, and enzyme activity in murine cells [148]. The likely explanation for this effect is an alteration in the levels of polyunsaturated fatty acids and their metabolites, reducing the availability of PPARγ-related ligands, such as linoleic acid, prostaglandin J2, etc. [148].
Several studies have also demonstrated a link between PPARγ
and the PI3K/Akt signaling pathway [148, 149], a well-known
pathway repressing catalase expression. Because PPARs undergoing nuclear translocation after ligand activation showed both
perinuclear and cytoplasmic distribution [150], the inhibitory effects triggered by PPARγ on the PI3K/Akt pathway may be indirect,
Table 1 also shows other transcription factors, namely Oct-1
and Nrf2 (nuclear factor (erythroid-derived 2)-like 2), playing a
role as potential activators of catalase expression. Their precise
involvement is difficult to establish because the experimental data
supporting their role are scarce and somewhat controversial.
The POU-domain transcription factor Oct-1 (POU2F1) regulates
a large group of target genes such Prdx2 (peroxiredoxin 2), Ifi202b
(interferon-activated gene 202B), and Timp3 (tissue inhibitor of
metalloproteinases-3) and acts as a sensor of oxidative and metabolic stress [154]. This factor binds to the human catalase promoter at the octamer consensus sequence ATTAAATA and positively regulates catalase expression (Fig. 1) [155]. Hypermethylation of the Oct-1 promoter led to a low expression of Oct-1 and
subsequently a decrease in catalase protein levels in hepatocarcinoma cells exposed to H2O2 [155].
It has been reported that Nrf2, a pleiotropic transcription factor
involved in cellular defenses against oxidative stress, increases the
expression of several antioxidant enzymes, including catalase
[156]. Conversely, their expression was significantly lower in various cell types derived from Nrf2 / mice compared to those from
wild-type control animals [157–159]. Nevertheless, because no
antioxidant-response element sequences were found in the catalase promoters and there is no evidence that Nrf2 can bind directly
to the catalase promoters, the involvement of Nrf2 in the regulation of catalase expression remains controversial.
Few transcription factors have been identified as repressors of
catalase gene transcription. Among them are WT1/Egr family
members (Figs. 1 and 2), HNRF (hepatocarcinogenesis-related negative regulatory factor), and ER transcription factors (Table 1).
Moreover, the PI3K/Akt/mTOR signaling pathway plays a major
role in catalase downregulation in human cancer cell lines (Table 1) by repressing Forkhead box family members and/or by activating an unknown nuclear repressor.
As previously mentioned, an additional transcription factor
acting as a repressor of catalase expression in cancer cells is WT1,
whose gene is located in human chromosome 11 in the vicinity of
the catalase gene [160]. WT1 can control the development of
several organs and tissues, by activation or repression of numerous
target genes, resulting in a wide variety of biological effects, including growth, differentiation, and apoptosis [161]. WT1 protein
can be detected as four isoforms generated by alternative splicing.
WT1 protein is part of the Cys2–His2 zinc finger transcription
factor family and shares nearly 60% homology with Egr1 at the
DNA-binding domain [162]. WT1 (in particular the WT1-KTS isoform) binds Egr1 or Egr-like protein in cancer cells [163, 164], and
a specific WT1 binding site has been proposed, namely
GCGTGGGAGT (called WTE), which displays 20- to 30-fold higher
affinity for the Egr binding sites [165]. Although it is not clear
which isoform is responsible for the repression of catalase expression [29, 55], the mechanism involved in this process may
include (i) competition with activator proteins, such as Spl or Egr1,
for GC-rich binding sites; (ii) reduction in the activity of nearby
bound activator proteins; and (iii) titration of cofactors required
for activation (“squelching”) [162].
In rat hepatoma cell lines, decreased catalase expression was
C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
related to the presence of a 20-kDa nuclear protein named HNRF
[166]. Using reporter and electrophoretic mobility-shift assays, it
was further shown that HNRF binds to the site sequence GATATCCCGATATC, located 3 kb upstream of the catalase gene (Fig. 1).
Interestingly, dedifferentiated rat hepatoma cells expressed this
factor, whereas well-differentiated cells did not, suggesting a role
for HNRF as a trans-repressor in the negative regulation of catalase
gene expression during liver carcinogenesis [166].
In addition to the transcription-activating factors previously
discussed in this review, we hypothesize that another factor may
be involved in the positive regulation of catalase expression. Based
on preliminary results, we postulate that Jun family proteins may
activate transcription of the catalase gene in human cells. The
predicted site for JunB is TGACCCA, located at position 1352/
1346 (from the ATG codon start) in the human catalase promoter (Fig. 3A). This predicted site is conserved among animal
species (Fig. 3B). Interestingly, there is a long insertion in the rat,
mouse, and macaque promoter sequences (not shown), suggesting
that the binding site does not exist in this particular region of the
promoter for these species. Two lines of evidence support this
hypothesis: first, using chromatin immunoprecipitation (ChIP)
assays, we showed that JunB binds to the human catalase promoter in the HepG2 and MCF-7 cell lines (Fig. 3C). Moreover, the
91
use of specific siRNA against JunB led to a decreased level of catalase in these cells (Figs. 3D and 3E). The exact molecular mechanisms by which JunB and other transcriptional regulators
mediate catalase transcription are currently under study.
2.5. Humoral factors
Several hormones may control catalase transcription. The first
studies reporting decreased expression of catalase by a humoral
factor were conducted in tumor-bearing mice. Indeed, decreased
levels of catalase were reported in liver tissues adjacent to transplanted tumors, but when tumors were removed, catalase expression returned to normal levels [167–169]. These results suggested that humoral factors produced by the tumors may regulate
the expression of catalase in surrounding normal tissues. However,
this phenomenon was not observed in other organs (e.g., the
kidney) and seemed to be restricted to liver cells [32].
Since these early studies, several hormones have been reported
to be involved in the regulation of catalase expression. For example, autocrine production of human growth hormone (hGH) in
mammary carcinoma MCF-7 cells positively regulates the expression of the catalase gene and other antioxidant enzymes, such as
superoxide
dismutase,
glutathione
peroxidase,
and
Fig. 3. The JunB transcription factor regulates positively catalase transcription. (A) Transcription factors controlling human catalase gene expression. The localization of
PPARγ, Oct-1, NF-Y, Sp1, and FoxM1 binding sites on the human catalase gene are listed in Table 1. The predicted site for JunB is TGACCCA, located at position 1352/ 1346
(from the ATG codon start) in the human catalase promoter. (B) Selected part (human JunB binding site TGACCCA) of the multiple sequence alignment of 12 catalase
promoters. Color scheme: blue, 475% sequence identity; green, 50–75%; yellow, 25–50%, and white, o 25%. The consensus sequence is obtained from the most frequent
nucleotide residues found at each position. (C) ChIP analysis using a JunB-specific antibody or an IgG control antibody to detect JunB occupancy at the promoter of the human
catalase gene in MCF-7 breast cancer and HepG2 hepatocellular carcinoma cell lines. Data are expressed as relative occupancy obtained with the following calculation: 2 EXP
(CT input CT ChIP 1500)/2 EXP (CT input CT ChIP þ 1000). The catalase gene region around nucleotide þ 1000 was used as a negative locus in which JunB binding sites
were not found. The relative occupancy can be considered as a ratio of specific signal (ChIP 1500) over background (ChIP þ 1000). (D) Western blots showing JunB knockdown
and catalase expression in human MCF-7 and HepG2 cell lines. β-Actin was used as a loading control. (E) Bands obtained via Western blot analysis were quantified, using
ImageJ software (National Institutes of Health, Bethesda, MD, USA). Catalase protein expression was normalized to that of β-actin and cells incubated with control siRNA. Data
are means 7 SEM, from three separate experiments. Data were analyzed using an unpaired t test, performed with GraphPad Prism software (GraphPad Software, San Diego,
CA, USA). *p o 0.05, **p o 0.01. Abbreviations: PPARγ, peroxisome proliferator-activated receptor γ; Oct-1, POU domain class 2 transcription factor 1; NF-Y, nuclear factor Y;
Sp1, specificity protein 1; and FoxM1, Forkhead box protein M1.
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C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
glutamylcysteine synthetase, in a p44/42 kinase-dependent manner [170]. Indeed, use of the MAPK inhibitor PD098059 abrogated
the effect of hGH on catalase regulation [170].
Steroid hormones also seem to regulate the expression of catalase. Indeed, in ER-positive MCF-7 breast cancer cells, the expression of catalase was decreased by exposing the cells to estrogens.
Conversely, tamoxifen (an estrogen receptor blocker) provoked the
opposite effect [171]. As expected, this effect was not observed in
ER-negative MDA-MB-231 breast cancer cells, confirming a putative
role of the estrogen receptor pathway in the regulation of catalase
expression [171]. Progesterone was shown to be a potent inducer of
catalase activity in both normal and breast cancer cells, an effect
mediated via the progesterone receptor B isoform [172].
Finally, the extracellular protein transforming growth factor β activates PI3K/Akt and SMAD3 (mothers against decapentaplegic
homolog 3) signaling pathways and decreased the protein levels of
catalase and superoxide dismutase in mouse airway muscle cells [173].
3. Other processes regulating catalase expression
Genetic alterations and epigenetic, posttranscriptional, and
posttranslational modifications have also been discussed as regulators of the transcription of the human catalase gene and are
summarized in Table 2.
3.1. Genetic alterations
Gene amplification, loss of heterozygosity, and deletion of
chromosomal arms are common genetic alterations detected in
tumors and cancer cells (Table 2).
Decreased activity of catalase has been observed in various
genetic alterations, for example, loss of alleles (i.e., loss of hete-
rozygosity) of the catalase gene in non-small-cell lung cancer cells
[160, 174, 175]; deletion of chromosome 11p, as has been observed
in children affected by Wilms tumor, aniridia, gonadoblastoma,
and retardation syndrome [176–182], and in later passages of
SV40-transformed human fibroblasts [183].
By contrast, increased expression of catalase may be explained
by either a gain of catalase gene copy or an amplification of
chromosome 11p. Gene amplification is a typical tumor genetic
alteration and cancer cells take advantage of this mechanism to
overexpress particular genes under stress conditions, such as exposure to cytotoxic drugs or oxidative stress [184]. Indeed, in human HL-60 leukemia and HA1 fibroblast cell lines rendered resistant to H2O2, the enhanced catalase activity correlated with an
increase in gene copy number in resistant cells compared to parental cell lines [56, 185].
As previously stated, several single-nucleotide polymorphisms
have been detected, and significant correlations with various diseases have been reported [21, 22]. Mutations in catalase protein
have been described in acatalasemic patients [21, 22], but no
mutations have been detected in the coding sequence, to our
knowledge, in patients suffering from cancer. To our knowledge,
only one polymorphism correlates with the transcriptional activity
of the catalase gene in cancer (Table 2). In the case of C-to-T
polymorphism at position 262 from the start of transcription
(330 bp upstream of the ATG translation start), the T variant
showed greater transcriptional activity in HepG2 and K562 cells
[186]. In patient samples, the TT genotype was associated with a
higher risk of hepatocellular carcinoma and reduced catalase activity [187]. Conversely, it was shown that CC homozygotes
had higher catalase activity compared to those with CT or TT
genotypes in breast cancer [188], but this study has been refuted
[189].
Table 2
Types of regulation that increase or decrease catalase protein levels
Type of regulation/ genetic event
Increased catalase protein levels
Gene amplification
262 C/T polymorphism (T variant)
Posttranscriptional
Posttranscriptional (RNA binding factors)
Decreased catalase protein levels
Loss of heterozygosity
Deletion of chromosome 11p
262 C/T polymorphism (T variant)
Histone H4 deacetylation
DNA hypermethylation
Posttranscriptional (RNA binding factors)
Phosphorylation of Tyr231 and Tyr386 residues
Cell/tumor type
Ref.
Human H2O2-resistant HL-60 promyelocytic leukemia cell lines
Chinese hamster H2O2-resistant HA1 fibroblasts
Human red blood cells from individuals
Human HepG2 hepatoma and K562 CML cell lines
Human breast carcinoma
Human H2O2-resistant MCF-7 breast cancer cells
Human fibroblasts
Rat PC12 pheochromocytoma cells
Mouse erythrocytes
[56]
[185]
[186]
[186]
[189]
[196]
[197]
[198]
[199]
Human non-small-cell lung carcinoma
Red blood cells from WAGR patients
WAGR patients
Human fibroblasts from WAGR patients
Human lymphocytes from WAGR patients
Human nephroblastoma patients
Human lymphoblasts from WAGR patients
Human SV40-transformed fibroblasts
Human hepatocellular carcinoma
Human breast carcinoma
Human doxorubicin-resistant acute myeloid leukemia cell lines
Human hepatocellular carcinoma cell lines
Human hepatocellular carcinoma
Human ARPE-19 retinal pigment epithelial cells
Rat hepatoma
Human MCF-7 breast cancer cell lines
Human embryonic kidney HEK293 cells
Mouse embryonic fibroblasts
[157, 174, 175]
[175]
[177, 178]
[179]
[180]
[181]
[182]
[183]
[188]
[189]
[192]
[193]
[194]
[200]
[201]
[202]
[203]
[202]
Abbreviations: WAGR, Wilms tumor, aniridia, gonadoblastoma, retardation; SV40, simian virus 40.
C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
Fig. 4. Various levels at which the expression of catalase may be regulated. Abbreviations: FoxM1, Forkhead box protein M1; Oct-1, POU domain class 2 transcription factor 1; PPARγ, peroxisome proliferator-activated receptor γ; NF-Y, nuclear factor Y; Sp1, specificity protein 1; FoxO3a, Forkhead box protein O3a; PGC-1α,
peroxisome proliferator-activated receptor coactivator 1α; XBP1, X-box-binding
protein 1; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; hGH, human growth hormone.
3.2. Epigenetic regulation
Gene transcription can be influenced by chromatin modulation
[190, 191]. In the case of the catalase gene, little information about
the role of epigenetic changes has been reported; however, histone
H4 deacetylation and DNA hypermethylation of the catalase gene
have been detected in hepatocellular carcinoma and acute myeloid
leukemia cell lines (Table 2). In this context, epigenetic changes
may regulate catalase expression in acute myelogenous leukemia
(AML) cells resistant to doxorubicin (AML-2/DX100), which exhibit
lower catalase protein levels compared to their parental cell lines
[192]. Inhibition of histone deacetylase activity increased catalase
protein levels in AML-2/DX100 cells [192]. As previously reported,
specific CpG islands in the human promoters of catalase and Oct-1
were methylated in human hepatocarcinoma cells after H2O2
treatment, which correlated well with decreased catalase expression in this model [155, 193]. Moreover, in liver carcinoma, the
catalase promoter is hypermethylated in the tumor itself but not in
the neighboring tissues [194]. DNA hypomethylation of the catalase gene is frequently observed in colon tumors, whereas few
modifications of DNA methylation are observed in breast adenocarcinomas compared to normal breast tissue [194, 195]. Analysis
of the DNA methylation pattern in patient tumor tissues shows
that the changes in the levels of DNA methylation occurred only
around exon 2 of the catalase gene [195].
3.3. Posttranscriptional and posttranslational regulations
The expression of catalase is also regulated at the RNA level.
Unidentified factors may protect or destabilize catalase mRNA. For
example, in MCF-7 cells that were rendered resistant to H2O2 and,
therefore, overexpressed catalase, delayed degradation of catalase
mRNA was observed (82% of catalase mRNA remained 24 h after
inhibition of RNA synthesis by actinomycin D in MCF-7/H2O2 vs
32% in MCF7) [196].
The 3′ untranslated region (UTR) of catalase mRNA has T-rich
clusters and CA repeats that are susceptible to regulation by unidentified redox-sensitive proteins that bind catalase mRNA and
enhance translation [197]. Because the half-life of catalase mRNA
is rather long (about 45 h), some unidentified proteins bind to the
93
5′UTR of the catalase mRNA to accelerate its translational rate, as
observed in PC12 cancer cells exposed to H2O2[198].
The micro-RNA miR-451 may enhance catalase expression by
suppressing protein 14-3-3, an inhibitor of the FoxO3a pathway
[199]. Conversely, miR-30b can bind directly to the 3′UTR of the
catalase mRNA on a conserved site (Table 2), leading to a drastic
decrease in catalase protein levels in ARPE-19 cells (a human
retinal pigment epithelial cell line) [200].
Moreover, posttranscriptional regulation of catalase synthesis
may be different in healthy compared to tumor tissues. For example, purified normal liver polyribosomes can synthesize catalase, whereas hepatoma polyribosomes cannot [201].
In addition to the previously mentioned regulatory processes
involved in catalase expression, the catalase protein itself may also
be regulated by posttranslational modifications affecting its levels
or its activity. Although this aspect has not been considered in this
review, posttranslational modifications, such as phosphorylation
and ubiquitinylation of this protein, regulate the turnover and
degradation of catalase. Indeed, in human cancer cells exposed to
oxidative stress, the tyrosine kinases c-Abl (Abelson murine leukemia viral oncogene homolog 1) and c-Abl-related gene are able
to phosphorylate human catalase at residues Tyr231 and Tyr386
(Table 2) [202, 203]. The phosphorylated enzyme is subsequently
ubiquitinylated and degraded by the proteasome [202, 203].
Finally, posttranslational modifications, such as phosphorylation (Ser167) [204], glycation [205], and acetylation [206], decrease catalase activity. Conversely, covalent binding of the enzyme to p53 [207] and ataxia telangiectasia mutated [208] proteins induces catalase enzyme activity.
Fig. 4 shows a summarized view of the previously discussed
levels at which catalase expression may be regulated. The first level
is represented by the transactivating activity of transcription factors,
their mutual cooperation with coactivators, and the activity of humoral factors. Other levels of regulation are represented by genetic
(loss of heterozygosis, gene amplification, and gene polymorphism)
and epigenetic (DNA methylation and histone H4 acetylation) processes. Finally, there are posttranscriptional processes (mRNA stability and micro-RNAs) affecting the levels of catalase RNA.
4. Developing strategies to modulate catalase protein levels
Altered expression of catalase has been associated with several
diseases [21, 22]. In the particular field of cancer pathology, increased and decreased expression of catalase have both been
reported.
In this context, a large body of evidence indicates that cancer
cells are frequently more sensitive to oxidative stress because of
their low levels of antioxidant enzymes (catalase, glutathione
peroxidase, superoxide dismutase, etc.) [23–35, 39–41]. Given the
increasing interest in the development of pro-oxidant therapies,
modifying the intracellular redox status of cancer cells by targeting
catalase may be an attractive and interesting approach to improve
the efficacy of cancer treatments [85, 87]. Indeed, because decreased expression of catalase in cancer cells will lead to increased
ROS generation, the use of pro-oxidant drugs may be an efficient
alternative to specifically eliminate cancer cells [84–87]. Therefore,
understanding the molecular mechanisms that regulate catalase
expression may be very important to improve pro-oxidant strategies. For example, the increase in some antioxidant enzymes,
such as SOD and catalase, can inhibit tumor cell growth and metastasis [12, 74]. Therefore, targeting PI3K/Akt/mTOR [209, 210]
may increase the expression of catalase in tumors and inhibit tumor cell growth. However, the efficiency of these promising anticancer strategies still needs to be proven in vivo and, especially, in
human clinical trials.
94
C. Glorieux et al. / Free Radical Biology and Medicine 87 (2015) 84–97
On the other hand, as previously mentioned in the introduction, increased catalase expression has also been observed in tumors [50–53]. Therefore, several approaches looking to decrease
both catalase levels and its activities have been developed. For
example, because catalase may be located on cancer cell membranes, the use of specific antibodies may inhibit this enzyme in
cancer cells and restore their ROS-mediated apoptotic signaling
pathways [20]. The use of specific siRNA coupled to nanoparticles
is another strategy to decrease catalase protein levels and to induce apoptosis in tumor cells [20]. PPAR antagonists (i.e.,
LY293111) [211] could be another alternative, in association with
pro-oxidant drugs, to decrease catalase protein levels and subsequently increase ROS production in cancer cells to improve their
response to chemotherapeutic drugs. Finally, considering the
multiple mechanisms involved in the regulation of catalase, an
additional method to decrease catalase activity in cancer cells is
direct enzyme targeting and the development of new, safe, and
specific catalase inhibitors.
5. Conclusions
In this review we have shown that the promoter region of
mammalian catalases was highly conserved during evolutionary
history allowing efficient binding of transcription factors NF-Y, Sp1,
and WT1/Egr in the core region. Various other factors, mainly the
Fox family members regulated by the Akt/PKB signaling pathway,
possess conserved binding sites in vertebrate catalase promoters.
Speciation events during evolution caused only small variations
within these regions, conserving heme catalase as an essential
housekeeping gene. Obviously different is the transcriptional
regulation of catalase expression in normal versus cancer cells. As
tumors are frequently more sensitive to oxidative stress and exhibit rather low levels of antioxidant enzymes, the development of
pro-oxidant therapies targeting mainly catalase may lead to improvements in cancer treatments.
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