ARTICLE
Auteur(s) : Vanessa Dehennaut, Dominique
Leprince
CNRS-UMR 8161, Institut de Biologie de Lille,
Université de Lille-Nord de France, Institut Pasteur
de Lille, IFR 142, 1, rue Calmette, BP447, 59017, Lille
Cedex, France
Article reçu le 14 Mai 2009, accepté le 14 Août 2009
HIC1 (Hypermethylated In Cancer 1) is a tumor suppressor gene
located in 17p13.3, a chromosomal region frequently hypermethylated
or deleted in cancerous tissues [1]. HIC1 is ubiquitously
expressed in healthy tissues whereas HIC1 is epigenetically
silenced in many human cancers. Moreover, the hypermethylation
level of the HIC1 promoter region (an epigenetic modification
responsible of gene silencing [2]) is variable and is in close
correlation with the aggressiveness of the tumor [3]. On the
biochemical point of view, the HIC1 protein is a
transcriptional repressor that is composed of three main functional
domains: a BTB/POZ protein-protein interaction domain (Broad
complex, Tramtrack and Bric à brac/POx viruses and Zinc finger) in
the N-terminal part of the protein, a central region which is not
phylogenetically conserved and a C-terminal domain containing five
Krüppel-like C2H2 zinc fingers that allows
the specific binding of the protein onto HIC1 responsive
elements (HiRE, GGCA consensus) in the promoter of its target genes
[4]. The BTB/POZ domain is an autonomous transcriptional repression
domain that is unable to recruit neither a class I nor a class II
HDAC (Histone Deacetylase) since it is insensitive to specific
inhibitors of these HDACs like trichostatin A (TSA) [5]. The
central region of HIC1 is also an autonomous transcriptional
repression domain but which is sensitive to TSA. It contains two
short phylogenetically conserved motifs:
- – GLDLSKK, that allows the recruitment of the
co-repressor CtBP (C-terminal Binding Protein) [6];
- – ΨK314xEP, whose lysine is competitively
targeted by acetylation and SUMOylation, a post-translational
modification which consists in the covalent attachment of one or
several SUMOs (Small Ubiquitin Related Modifier) proteins on lysine
residues of the target protein.
The competition between these two post-translational
modifications (PTM) regulates, in part, the repressive activity of
HIC1 [7] (figure
1). To date, only five HIC1 targets genes have been
identified:
- – the histone deacetylase SIRT1 (Sirtuin 1) [8];
- – FGF-BP1 (Fibroblast Growth Factor Binding Protein 1),
a FGF binding protein that contributes to endothelial cells
proliferation and to smooth muscular cells differentiation
[9];
- – Atoh1, a transcription factor implicated in the
development of medulloblastoma [10];
- – the transcription factor E2F1 [11];
- – CXCR7 (Scavenger Chemokine (CXC Motif) Receptor 7), a
scavenger receptor for the chemokine SDF-1/CXCL12 [12].
Hic1 +/- heterozygous mice develop late in their life a
gender-specific spectrum of spontaneous tumors [13]. In fact, in
these mice, the promoter region of the remaining wild type allele
becomes hypermethylated on CpG islands leading to its inactivation
and favoring the appearance of tumors. In addition, the analysis of
Hic1+/- p53+/- double-heterozygous mice has demonstrated the
existence of a cooperation between HIC1 and p53 since
HIC1 alteration leads to modifications of the incidence, of the
virulence and of the spectrum of tumors in comparison to p53+/-
mice [14]. In addition, several studies tend to demonstrate that,
in vivo, the cell DNA damage response depends on several complex
regulatory loops implicating HIC1 and p53, but also
SIRT1 and E2F1, both being HIC1 targets (figure 2).
HIC1 is a p53 target gene during the DNA damage response
The transcription factor p53 is indubitably considered as the
guardian of the genome. In aproximately 50% of cancers p53 is
mutated and the development of anti-cancer drugs that restore its
activity is a rapidly growing research domain [15]. In response to
numerous cellular injuries including DNA damage, p53 is
quickly stabilized and activated through many kinds of
post-translational modifications. In its activated form,
p53 transactivates many target genes implicated in DNA damage
repair (DDR), cell cycle arrest (as long as the repair is not
completed) and apoptosis (in the case of irreparable damage).
A p53 responsive element (PRE) was identified in the
promoter region of HIC1 suggesting that HIC1 is a direct
p53 target gene [1, 16, 17]. Exogenous expression of
p53 in the p53-/- osteosarcoma cells SAOS-2 induces the
expression of the two HIC1 transcripts [16]. In the
p53 +/- human colon cancer SW480 cells, the HIC1 promoter
region is hypermethylated. Nevertheless, in these cells, exogenous
expression of p53 also causes an increase in
HIC1 transcription associated with cell growth arrest [1]. The
authors conclude that p53 can activate the transcription of
HIC1, independently of its methylation status, although one cannot
exclude that the observed effect is due to the overexpression of
p53 and that this phenomenon does not effectively occur under
physiological levels of p53. In addition, elevated levels of
HIC1 transcripts were observed by Britschgi et al. upon
irradiation of MCF7 cells (p53 +/+ breast cancer cells)
but not in MCF7 cells in which p53 expression has been
knocked-down by RNA interference (RNAi) [17]. Moreover, an increase
in HIC1 transcripts and proteins has been demonstrated in
U87MG cells (p53+/+ glioblastoma cells) upon serum starvation or
cisplatin-induced cell cycle arrest [18]. Such an increase has
never been observed in U87MG cells expressing a “dominant-negative”
form of p53. Taken together, these two studies suggest that
p53 transactivates HIC1 in response to DNA damages and one
could anticipate that HIC1 regulates the p53-mediated
apoptosis. Indeed, mouse embryonic fibroblasts knocked-out for
HIC1 (Hic1 -/- MEFs) are more resistant to the treatment with
the chemotherapeutic agent etoposide (that provokes DNA
double-stranded breaks) than wild-type MEFs [8]. Conversely,
infection of MCF7 cells with an adenoviral vector expressing
HIC1 brings about apoptosis upon etoposide treatment whereas
cells infected with a control vector are resistant to the drug.
However, over-expression of HIC1 in p53 null cells has no
effect on DNA damage-induced apoptosis indicating that HIC1 is
not sufficient to trigger apoptosis of damaged cells but that
HIC1 acts in synergy with p53 to monitor the DNA damage
response [8]. DNA double-stranded breaks rapidly induce
phosphorylation of the histone H2AX by the ATM kinase (Ataxia
Telengectasia Mutated). Then phosphorylated H2AX, henceforth called
γH2AX, binds to DNA breaks and forms γH2AX foci to allow the
recruitment of DNA repair proteins [19, 20]. In their study, Chen
et al. have shown that γH2AX foci were normally formed in Hic1
-/- MEFs and in MCF7 cells thus suggesting that HIC1 does
not take part in the initiation of the DNA damage response [8].
HIC1, in association with SIRT1, regulates the DNA damage
response
HIC1 can form a transcriptional repression complex with SIRT1
[8]. The two proteins directly or indirectly interact through the
BTB/POZ domain of HIC1. This complex binds to the SIRT1 promoter to
repress its transcription through incompletely deciphered
mechanisms [8]. SIRT1 is an NAD+- dependent class
III HDAC that deaceylates histones (H1K26; H3K9; H4K16) but also
several non histone proteins including p53 [21], E2F1 [22] and HIC1
[7]. Deacetylation of p53 lysine 382 decreases the
transcriptional activity of the protein towards its target genes,
one of them being HIC1 [8]. The recruitment of SIRT1 by
HIC1 would thus be essential for the progress of DNA
damage-induced apoptosis. In fact, a truncated form of
HIC1 lacking the BTB/POZ domain is unable to induce apoptosis
of MCF7 cells after etoposide treatment. Hic1 -/- MEFs
expressing catalytically inactive SIRT1 mutants (mutant H355A or
H363Y) no longer resist to etoposide and, in normal
WI38 fibroblasts, the knock-down of HIC1 by RNAi provokes a
decrease in etoposide-induced p53 acetylation in correlation
with an increase in SIRT1 expression [8]. Taken together these
results thus suggest that the inhibition of SIRT1 transcription by
the HIC1/SIRT1 complex is essential for the DNA damage-induced
cell death. The activity of SIRT1 depends upon its SUMOylation
status [23]. Yang et al. demonstrated that SIRT1 is
SUMOylated at the lysine 734 in numerous mammals except mice
[23]. In this study, the authors demonstrated that during the UV-
or hydrogen peroxide-induced apoptosis, SENP1 (SUMO 1/sentrin
specific peptidase 1) deSUMOylates SIRT1, deactivates the
deacetylase and allows the subsequent acetylation of some target
proteins, including p53. Intriguingly, SIRT1 is also a
p53 target gene [24] that suggests the existence of a complex
equilibrium between the two proteins during the DNA damage response
(figure 2).
SIRT1 also represses the activity and/or expression of several
DNA repair proteins like the DNA helicase Ku-70, or, the
transcription factors of FOXO family, suggesting that SIRT1 can act
as an oncogene by preventing the cellular DNA damage response in
both a p53-dependent and independent ways [25]. In contrast,
several recent studies tend to demonstrate that SIRT1 could
also act as a tumor suppressor favoring the DNA damage response. In
embryonic mice fibroblasts, the invalidation of SIRT1 disrupts the
DNA damage repair, in particular, ionizing radiations-induced γH2AX
foci formation although the absence of SIRT1 has no effect on
the activity of the ATM/Chk2/p53 pathway that is on the
phosphorylation of H2AX per se [26]. SIRT1 would thus play an
important role in the recruitment of γH2AX on the sites of breaks.
This hypothesis is reinforced by the fact that exposure of
embryonic stem cells to hydrogen peroxide or to ionizing radiations
leads to the relocation of SIRT1 on DNA double-stranded break
sites whereas the knock-out of SIRT1 in these cells disrupts DNA
repair [27]. Our team identified a ΨK314xEP motif in the
HIC1 central region that permits the post-translational
modification of the same lysine residue (K314) by SUMOylation or
acetylation [7] (figure
1). Moreover, the competition between these two PTMs is
orchestrated by a new type of complex built up by two deacetylases
belonging to different functional classes, HDAC4 and SIRT1.
Indeed, HIC1 is acetylated by CBP/p300 whereas
SIRT1 deacetylates HIC1 on lysine 314. This residue then
becomes accessible for SUMOylation which is favored by a class II
histone deacetylase, HDAC4, according to a mechanism that remains
to be deciphered but that seems independent from the deacetylase
activity of the protein. The SUMOylation of HIC1 is essential
for its activity since its abolition (K314R or E316A mutants)
diminishes the transcriptional repression potential of HIC1 [7].
Thus, the interaction between HIC1 and SIRT1 would allow
the repression of HIC1 target genes, on the one hand by the
HDAC activity of SIRT1 per se (H4K16 or H3K9) even though
it was never clearly demonstrated [8] and on the other hand by the
formation of a HIC1/SIRT1/HDAC4 complex allowing the
deacetylation followed by the subsequent SUMOylation of
HIC1 and the recruitment of different co-repressors by HIC1.
So, one can suppose that a correct DNA damage response would
require in part a kinetic of activation and repression of SIRT1:
first of all, its activity would be necessary to optimize the
repressive capacity of HIC1 and to favor the formation of the
γH2AX foci, then its transcriptional repression would allow the
activating acetylation of p53 (figure 2). Other
inhibitory mechanisms of SIRT1 in response to DNA damages have
been described such as prevention of its transcription by the
micro-RNA miR-34a whose expression is under the control of p53 [28]
or inhibition of its activity through its interaction with
DBC1 (Deleted in Breast Cancer 1) [29, 30]. It would be
interesting to study if HIC1 could interfere with these
mechanisms.
A HIC1/E2F1 auto-regulatory loop could also contribute to the
DNA damage response
E2F1 is above all known to regulate the transcription of genes
involved in the G1/S transition of the cell cycle and thus to
promote cell proliferation. Paradoxically, a large number of
studies have shown that E2F1 is also an important regulator of
apoptosis. In response to DNA damages, E2F1 is stabilized
thanks to its phosphorylation by the ATM/ATR (Ataxia Telangectasia
Mutated/Related) and Chk2 (Checkpoint kinase 2) kinases (also
responsible for the stabilization of p53) and to its acetylation by
PCAF (p300/CREB-binding protein associated factor). The
E2F1-induced cell death involves various signaling pathways:
- – in a p53-dependent manner by activation of p14ARF,
which associates with Mdm2 to prevent the ubiquitination and the
proteasomal degradation of p53;
- – independently of p53 through the transcriptional
stimulation of p73 (a protein of the p53 family [31]) and Apaf-1
(apoptosis protease-activating factor 1), the latter interacting
with cytochrome c to form the apoptosome and to activate procaspase
9 [32].
Moreover, in response to DNA damages, E2F1 can interact
with DNA repair proteins such as Nbs1 (Nijmegan breakage
syndrome 1), BRCA1 (BReast CAncer gene 1) or
TopBP1 (Topoisomerase IIβ Binding Protein 1) that locate
E2F1 on the DNA breaks sites [32]. This suggests that
E2F1 would also have a role in the repair of the damaged DNA
independently of its transcriptional activity. Very recently, two
studies demonstrated the existence of a feedback loop between
HIC1 and E2F1 [11, 33] (figure 2). Two
E2F1 responsive elements (ERE1 and ERE2) have been
identified upstream of one of the two HIC1 promoters [33].
These ERE are phylogenetically conserved between human, rat and
mouse and chromatin immunoprecipitation (ChIP) experiments have
confirmed the binding of E2F1 on these EREs. In this work, the
authors demonstrated that HIC1 is a direct E2F1 target gene in
p53 -/- hepatocarcinoma HEP3B cells while the EREs are
hypermethylated. They also observed a dose-dependent increase of
HIC1 transcripts upon etoposide treatment of these cells
whereas this increase is reduced when expression of E2F1 is
decreased using RNAi. This suggests that E2F1 induces the
expression of HIC1 in response to DNA damage independently of p53.
Conversely, HIC1 represses the transcription of E2F1 in
quiescent fibroblasts [11]. Interestingly, Zhang et al.
demonstrated that this transcriptional repression requires the
interaction of HIC1 with Brg1, an ATP-dependant chromatin
remodeling protein belonging to the SWI/SNF complexes family [11].
These complexes are associated with the transcriptional regulation
of numerous genes implicated in cell cycle regulation and in
double-stranded DNA breaks repair [34]. Thus, one can propose that
in response to DNA damage, E2F1 induces the transcription of
HIC1 which in turn and in association with some SWI/SNF complexes
represses the expression of E2F1 succeeding in the
establishment of a negative feedback loop between these two
proteins. SIRT1 is also a direct E2F1 target gene during
etoposide-induced DNA damage response [22] and similarly a negative
feedback loop seems to exist between E2F1 and SIRT1 (figure 2). Indeed,
the authors demonstrated that SIRT1 interacts with
E2F1 resulting in the subsequent deacetylation of the
transcription factor and in its inactivation. This SIRT1/ inactive
E2F1 complex binds to the auto-regulatory site in the
E2F1 promoter (which is stimulated by E2F1) to repress its
transcription. Furthermore, the exogenous expression of
SIRT1 prevented the E2F1-induced apoptosis in a “p53 wild
type” or a “p53 null” context while the nicotinamide-induced
SIRT1 inhibition sensitizes cell to etoposide. These results
suggest that SIRT1 inhibits the pro-apoptotic function of
E2F1. A very recent study showed that SIRT1 would
regulate more particularly the PCAF-E2F1-p73 pro-apoptotic
pathway (independent of p53) [35]. SIRT1, PCAF and E2F1 are
co-recruited on the p73 promoter and prevent its
transcription. This complex is found on this promoter independently
of DNA damage induction. However, the activity of
SIRT1 depends on the NAD+/NADH+ ratio
present in the cell and in a simple way, the authors demonstrated
that in the condition of DNA damages, the modulation of the
cellular “redox” status provokes an inhibition of the deacetylase
activity of SIRT1 that allows the transcription of
p73 without releasing it from the p73 promoter.
Conclusion and future directions
The correct response of the cell faced with DNA damage is crucial
to maintain the genome integrity and avoid the transmission of
genetic aberrations during cell division. This response requires
the establishment of a complex balance between activations and
repressions of key proteins. Besides p53, it becomes increasingly
clear that HIC1 also plays a central role in this phenomenon
due to the existence of several regulatory loops, implicating this
transcriptional repressor and two of its target genes SIRT1 and
E2F1. So, we can easily suppose that during the early
tumorigenesis, the epigenetic inactivation of HIC1 could induce an
increase of the deacetylase activity of SIRT1 associated with
an inactivation of p53 and E2F1 among others, and could
allow the cancerous cell to escape from the cell cycle arrest or
apoptosis normally induced upon DNA damage. To sustain this
hypothesis, it has been very recently brought to the fore that
deregulations of the HIC1-SIRT1-p53 loop were associated with
poor prognosis of patients with lung squamous cell carcinoma and
lung adenocarcinoma [36]. However, numerous questions remain
unresolved as for the precise involvement of HIC1 in this DNA
damage response: more particularly, the identification of other
HIC1 target genes as well as the knowledge of the mechanisms
of regulation of its transcriptional activity.
Acknowledgments
We would like to thank Pr. Tony LEFEBVRE for the critical reading
of the manuscript. We would also like to thank the CNRS, the
Pasteur Insitute of Lille, the “Association pour la Recherche sur
le Cancer” (ARC), the “Ligue Nationale Contre le Cancer”, the
“Fondation pour la Recherche Médicale (FRM) comité Nord-Pas de
Calais” for their financial support. VD is a recipient of a
post-doctoral fellowship from ARC.
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