The
Role of Epigenetic Modulation in the Cellular Response to Ionizing Radiation
Dong
Pan, Yarong Du, Burong Hu
Dong
Pan, Yarong Du, Burong Hu, Department
of Space Radiobiology, Key Laboratory of Heavy Ion Radiation Biology and
Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou
730000, China
Dong
Pan, University of Chinese Academy of
Sciences, Beijing, 100049, China
Correspondence to: Burong Hu PhD, Department of
Space Radiobiology, Key Laboratory of Heavy Ion Radiation Biology and
Medicine,Institute of Modern Physics, Chinese Academy of Sciences, 509 Nanchang
Road, Building 5-204, Lanzhou 730000, China.
Email: hubr@impcas.ac.cn
Telephone: +86-18509316339 Fax:
+86-0931-4969169
Received: March 13, 2015 Revised: April 6, 2015
Accepted: April 8, 2015
Published online: June 2, 2015
ABSTRACT
More and more
evidence demonstrate that epigenetic modulation plays important roles in many
cellular processes and carcinogenesis. It also showed that epigenetic changes
are involved in the cellular response to ionizing radiation. In current review,
we will discuss the radiation-induced epigenetic modifications including DNA
methylation changes, chromatin remodelling and alterations in microRNA expression,
and their roles in the cellular response to ionizing radiation. The aim is to
help understand the mechanisms underlying the radiation induced biological
effects in cells and to find the future research interests.
© 2015 ACT. All
rights reserved.
Key words: Epigenetic modulation; DNA methylation; Chromatin
remodelling; MicroRNA; Ionizing radiation
Pan D, Du YR, Hu BR. The Role of Epigenetic Modulation
in the Cellular Response to Ionizing Radiation. International
Journal of Radiology 2015; 2(1): 1-14 Available from: URL:
http://www.ghrnet.org/index.php/ijr/article/view/1109
Introduction
Epigenetic alterations are heritable changes underlying gene expression
by regulating the structure and function of the genome that are not caused by
alterations in the DNA sequence itself. It includes an array of molecular
modifications such as DNA methylation, chromatin remodelling, histone
modifications, genetic imprinting, random chromosome(X) inactivation and
noncoding RNA (microRNA, lincRNA and siRNA, etc) regulated gene expression[1].
The principal mechanisms of epigenetic changes are alterations in DNA
methylation and alterations to the packaging of DNA around the core histones,
both of which can result in gene activation or repression[2,3].
Epigenetics
plays important roles in many cellular processes from gene expression to
cellular proliferation and an aberrant epigenetic state in cells can result in
carcinogenesis[4]. Changes in genomic DNA methylation
post-irradiation and its potential correlation with cellular response have been
indicated[5-7], and changes in expression profiles of microRNA (miRNA)
have been observed following irradiation in mouse and human cells. These
evidences suggests that epigenetics may be the core mechanistic link between
irradiation and cellular response. Here, we mainly review the DNA methylation
changes, chromatin remodelling and alterations in miRNA expression, and their
roles in the cellular response to ionizing radiation (IR).
DNA
methylation
DNA methylation is one of the most important epigenetic modifications
of the genome involving in the regulation of numerous cellular processes
through gene silencing without altering DNA sequences. It is the most
extensively studied epigenetic mechanism and refers to the addition of a methyl
group (-CH3) to the carbon 5 position of cytosine ring in a CpG dinucleotide by
DNA methyltransferase (DNMTs)[8,9]. The remaining CpG dinucleotides
in the mammalian genome are often methylated. CpG dinucleotides are not
uniformly distributed throughout the human genome. Rather, they are
concentrated in specific regions (CpG islands) that are located in the upstream
region from the transcriptional start site of many genes as well as at other
regions. In human, approximately 60% of all genes have CpG islands in their
promoter regions, and these promoter associated CpG islands are generally unmethylated
in normal cells, with the exception of genomic imprinting, X-chromosome
inactivation or tissue specific gene hypermethylation[10,11]. Cancer
research in epigenetics in the 1990s was dominated by a focus on understanding
and extending the discoveries of DNA methylation abnormalities[4].
DNA methylation plays a central role in the epigenetic control of genomic
programs in both normal and cancer cells[12]. Of which the majority
is unmethylated in all normal tissue types and throughout development, which
was demonstrated by using computational analyses[13].
In mammals,
there are four types of DNMT: DNMT1, DNMT2, DNMT3a and DNMT3b. DNMT1 functions
as the maintenance methyltransferase by copying the methylation pattern of the
old DNA strand onto the newly synthesised strand during DNA replication[14].
In cancer and embryonic stem cells unmethylated CpG sites are targeted for de
novo methylation by DNMT3a and DNMT3b[15]. Information about
Dnmt2-dependent methylation patterns has been limited to a few isolated loci
and the results have been discussed controversially. In mammals DNMT2 is not a
DNA methyltransferase. It was shown that Dnmt2 has a robust methyltransferase
activity toward cytosine 38 in the anticodon loop of tRNA-Asp and other tRNAs
and that the enzyme uses the conserved DNA methyltransferase mechanism to
methylate tRNA[16]. In agreement with this notion, several
independent phylogenetic analyses have suggested that Dnmt2 is an ancient DNA
methyltransferase that has switched its substrate specificity from DNA to tRNA[16-18].
The DNMT2 protein methylates C38 of tRNA-Asp and it has a role in cellular
physiology and stress response and its expression levels are altered in cancer
tissues[19].
In cancer
cells, the promoter-associated CpG islands of tumor suppressor genes (TSGs) may
be aberrantly methylated (or hypermethylated), thereby promoting recruitment of
methyl-binding domain proteins, and histone-modifying and chromatin-remodeling
complexes to the methylated promoter-associated CpG sites[20]. This
renders formation of a compact chromatin configuration, precluding access of
transcription factors and hence transcriptional silencing of the corresponding
TSGs[21]. Therefore, DNA methylation is an important mechanism
leading to the inactivation of protein-coding or noncoding genes in human
cancers. Promoter regions of TSGs are hypomethylated to allow their expression
and maintain the normal state of the cell[12]. Cells that have
mutations in DNMT lack the stabilise effect of DNA methylation and have
prominent nuclear abnormalities[22].
DNA
methylation and radiation
DNA methylation is one of the most common mechanisms of epigenetic
regulation. Accumulating evidence suggests that changes in methylation patterns
may help mediate the sensitivity or resistance of cancer cells to IR. The
present studies provide evidence for the involvement of radioresistance-induced
DNA methylation changes in tumor radioresistance. There are multiple reports of
altered DNA methylation patterns following exposure to IR in plants, rodents,
and rodent and human cell lines[5,6,23-28]. Plants when exposed to
IR showed dose-dependent hypermethylation[29]. IR exposure has been
found to have dose-dependent, sex, and tissue-specific effects on global
hypomethylation using mouse model system[30]. Mostly
hypomethylation, loss of methylation, paralleled with a decrease in the DNA
expression levels of methyltransferases (DNMTs; DNMT1, DNMY3a, and DNMT3b) and
methyl CpG binding proteins (MeCP2) was associated with radiation-induced
changes[25,29].
In many of
these studies, the global DNA hypomethylation observed post-irradiation along
with the decreased expression of proteins involved in maintaining the correct
genomic methylation patterns suggest that these changes might play a role in
cellular response[6,25,29]. X-ray irradiation of mice was also shown
to affect methylation of the promoter of the p16 tumour suppressor in a sex-
and tissue-specific manner, but not the methylation status of O-6-methylguanine-DNA
methyltransferase (MGMT)[31]. It was suggested that the
radiation-induced hypomethylation patterns might result in genomic instability
and reshuffling of the hereditary material via chromosomal instability or
reactivation of transposable elements, allowing the cells to survive in the
radiation environment.
DNA damage and
genomic instability were manifested as reproductive cell death, reduced cloning
efficiency at successive passages, increased apoptosis, and an increased
proportion of chromosome aberrant cells after irradiation, while the cellular
responses to ionizing radiation are shown to be predominantly associated with
DNA hypermethlyation of certain CpG dinucleotides and pericentromeric
spermidine N1-acetyltransferase 2 (SAT2) satellite sequences. Non-specific DNA
hypomethylation is also observed. The majority of the hypermethylated sequences
detected are repeat elements. Aberrant methylation status of repeat elements
and SAT2 satellite sequences are known to affect cell survival and genomic
instability[32,33]. Based on these observations, the authors
suggested that methylation alterations following radiation exposure are
involved in.
Exposures to
low linear energy transfer (LET) gamma-rays (-rays) were also shown to result in
dose-dependent global hypomethylation in the C-1300 N1E-115 (mouse), CHO K-1
(hamster), V79A03 (hamster), and Hela S-3 (human) cell lines[23].
However, another study using one of the same cell lines, CHO K-1, showed no change
in methylation after X-ray exposure[5]. The different outcomes in
these two studies might suggest differences in changes in epigenetic profiles
after different types of radiations. The latter study also showed global
hypomethylation in mouse liver tissue after X-rays exposure but demonstrated no
change in mouse brain or spleen tissue[5]. Even though each of these
studies was performed post-low LET irradiation, different responses were
observed.
There are
interesting reports on the relationship between a DNA methyltransferase
inhibitor (5-aza-2'-deoxycytidine) and radiation sensitivity in colon cancer.
Genomic hypomethylation induced by 5-azacytidine results in enhanced radiation
sensitivity in coloncancer[34,35]. Promoter-CpG islands of five
previously identified radioresistance-related genes (TOPO2A, PLXDC2, ETNK2,
GFI1, and IL12B) were significantly altered in the radioresistant laryngeal
cancer cells. Furthermore, the demethylation of these gene promoters with a DNA
methyltransferase inhibitor (5-aza-2'-deoxycytidine) increased their
transcription levels. Treatment with 5-aza-2'-deoxycytidine also sensitized the
radioresistant laryngeal cancer cells to irradiation, indicating that changes
in DNA methylation contributed to their radioresistance[36]. In
addition, breast cancer cells treated with fractionated IR showed several
locus-specific DNA methylation alterations, which were mostly loss of
methylation (TRAPP9, FOXC1, and LINE1)[37]. Together with the
evidence for altered promoter methylation in particular cancers[32,38],
these data provide a link among radiation exposure, epigenetics and
carcinogenesis. Radiation-induced global DNA hypomethylation and promoter
hypermethylation may play roles in the maintenance of the genomic instability.
So far,
studies have already indicated the global hypo- and hypermethylation changes in
the irradiated cells. However, it remains to know which genes in methylation
changes are more important for cells after irradiation.
Chromatin
remodelling
Chromatin remodelling is involved in many biological processes
including gene expression, DNA replication and repair, chromosome condensation,
segregation and apoptosis[39]. Gene transcription is controlled by
histone modifications in chromatin. Positioning of the nucleosome with its 147
base pairs of DNA wrapped around the octamer of the core histones, H2A, H2B,
H3, and H4, in conjunction with the above modifications of histones, modulates
the normal epigenome in terms of maintaining gene expression patterns and
normal chromosome structure and function[40].
Carcinogenesis
not only alter DNA methylation but also cause global changes in the levels of
proteins that participatein chromatin modifications, polycomb-complex
components, and in histone modifications by acetylation and methylation of
lysine residues on histones H3 and H4[41,42]. The strong dependence
between DNA methylation and chromatin modifications for DNA packaging is known.
Furthermore, histone modification and DNA methylation closely interact in the
setting of the transcriptional states of chromatin. Especially in cancer cells,
silenced genes regulated by DNA hypermethylation can be models to examine the
chromatin control of gene expression. When such genes are expressed with no
methylation, their promoters have virtually identical distribution of the
active marks, H3K9acetyl and H3K4me[30,43]. In contrast, when
silenced genes are associated with hypermethylation, the distribution of these
active marks is severely decreased, and virtually every histone methylation
mark, including mono-, di-, and trimethylation of H3K9 and H3K27 that has been
associated with transcriptional repression, is enriched[30].
Phosphorylation of histone H2AX at serine 139 (H2AX) is one of the most extensively studied histone
modifications[44]. H2AX is used as an early marker for induction and repair of DNA
double-strand breaks[45,46]. It also appears to play a functional
role in the DNA repair process, maintenance of genome stability, and the early
stages of cancer[47,48].
Histone
deacetylases (HDACs) catalyze the removal of acetyl groups on the histone tail,
resulting in a transcriptionally inactive heterochromatic state[11].
Likewise, SIN3A (part of an HDAC repressor complex) is downregulated in NSCLC[49].
Relative to normal lung cells, lung cancer cells undergo H4K5/H4K8
hyperacetylation, H4K12/H4K16 hypoacetylation, and H4K20me3. Lower global
levels of H4K20me3 can be detected in precursor lesions and is particularly
common in squamous cancers[50].
Epigenetic
silencing of transcription also occurs through post-translational histone
modification, chromatin remodelling and changes in the nuclear positioning of
genes[18]. Deregulation of these and other chromatin processes have
been linked to the development and progression of cancer[39,51,52].
Some chromatin remodelling modifications observed in cancer cells are
alterations in the histone acetyation/deacetylation balance, increased or
decreased poly-adenosine diphosphate (ADP)-ribosylation band failures in
ATP-dependent chromatin remodelling mechanisms[53]. Deregulation of
histone acetylation can lead to carcinogenesis in three ways. Histone
hypoacetylation at certain promoter regions, induced by decreased HAT activity
or increased HDAC activity, can silence tumour suppressor genes. Conversely,
histone hyperacetylation at other promoter regions, induced by elevated HAT
activity or decreased HDAC activity, can lead to the activation of oncogenes.
Thirdly, carcinogenesis can be triggered by aberrant recruitment of HAT or HDAC[11].
Chromatin
remodelling and radiation
IR induced DNA damage response generally occur in
special euchromatic and heterochromatic regions. Chromatin immunoprecipitation
(ChIP) and immunofluorescence analysis were used to explore the distribution of H2AX. ChlP
experiments showed higher H2AX signal after IR in histone H3 trimethylated
lysine 4 (H3K4me3), compared to lysine 9 (H3K9me3) enriched chromatin
fragments, and this strengthen the dependence of IR-induced DNA damage response
on the chromatin region[54]. However, few studies try to investigate
the radiation-induced histone modifications to indicate the epigenetic
mechanism.
Radiation-induced phosphorylation of H2AX was extensively studied
as a measure of DSB accumulation in irradiated cells[55,56]. H2AX
accumulates in the nucleus at DSBs forming the H2AX loci, and a direct
correlation has been found between H2AX phosphorylation and the number of DSBs resulting
from radiation. Therefore, H2AX is crucially important for the repair of DNA
strand breaks and for the maintenance of genome stability[44].
X-ray irradiation in a mouse model induced a decrease in trimethylation
of histone H4K20 in the thymus and, eventually, resulted in an overall
relaxation of the chromatin organization in cells. In addition,
gamma-irradiation can result in relaxation of the chromatin structure around
the DSB immediately after exposure. However, after some time, the methylation
of H3K9 increased and the chromatin restored to the condensed state[57].
The epigenetic mechanisms on histone modification after radiation exposure
still remain to be explored.
In mice, radiation exposure led to decreased trimethylation of histone
H4 lysine which might result in relaxed heterochromatin organisation and would
impair genome stability[26]. It has been shown in human cells that
euchromatic regions were more susceptible to radiation-induced DNA damage and H2AX
accumulation[58-60]. Cells exposed to -rays showed chromatin
decondensation at sites of double-strand breaks[61]. The changes
were manifested as a decrease in intensity of chromatin labeling, increased
histone H4 lysine 5 acetylation, and decreased histone H3 lysine 9
dimethylation. Forty minutes post-irradiation, these changes induced by
radiation exposure were replaced by histone modifications typical for condensed
chromatin (decreased acetylation of histone H4 lysine 5 and increased
methylation of histone H3 lysine 9). The data suggested a requirment to convert
from less to more condensed chromatin after DNA repair. Another study observed
rapid binding of SWI/SNF complexes to chromatin in regions of double-strand
breaks via interaction with H2AX, suggesting that the repair mechanisms were
facilitated by SWI/SNF complex promotion of H2AX phosphorylation[29].
The role of ataxia telangiectasia mutated (ATM) in some of the chromatin
changes in response to radiation and as a result its potential role in cellular
response to ionizing radiation have been implicated[63]. In response
to double-strand break induction, Kruppel-associated box (KRAB) associated
protein (KAP-1) is phosphorylated in an ATM-dependent manner[64].
Phosphorylated KAP-1 leads to eu-chromatinisation. Therefore, these results
suggested that chromatin relaxation is a fundamental pathway in the DNA damage
response and that ATM and KAP-1 are its primary mediators. It was also
suggested that ATM-dependent heterochromatin relaxation is specifically
required for the repair of double-strand breaks located within heterochromatin[65].
Another study identified another signaling cascade that helps initiate the DNA
damage response by altering chromatin[66]. These studies indicate
that exposure to radiation affects chromatin remodelling in association with
DNA damage and DNA repair. Radiation-induced aberrations in chromatin
remodelling can lead to DNA damage and impaired DNA repair. This compromised
DNA repair and relaxed heterochromatin contribute to the initiation of genomic
instability.
MicroRNA
MicroRNAs (miRNAs) belong to a class of single
strand, small noncoding RNAs of 19-25 nucleotides (nts) in length that regulate
diverse developmental and pathological processes in eukaryotic organisms[67-69].
It can regulate negatively the expression of up to hundreds of messenger RNA
(mRNA) targets and are dysregulated frequently in lung cancer. Depending on
their genomic locations, miRNA genes can be transcribed from two different
pathways: intergenic miRNAs are transcribed by RNA polymerase II as primary
miRNAs (pri-miRNAs) with independent transcription units. The primary
transcripts (pri-miRNAs) are generated by polymerase II and stabilized by 5'
capping and 3' polyadenylation[70]. The distinct hairpin secondary
structure of pri-miRNA is recognized by the microprocessor complex (Drosha and
DGCR8) and then specifically cleaved at the base of stem-loop releasing a 60-80
nts pre-miRNA. A pre-miRNA of the hairpin or stem-loop structure is exported
into cytoplasm by exportin 5, and further processed and cleaved by Dicer to
yield the mature miRNA. Mature miRNAs lead to translational repression or mRNA
degradation of the target protein-coding genes by binding to complementary sequence
within 3' untranslated region (3' UTR) of their target mRNAs[71].
After completing its task, the mature miRNA is degraded by the 5'-3'
exoribonuclease or 3'-5' exoribonucleases. In cancer cells, approximately 50%
of annotated miRNA genes are mapped to fragile sites of the human genome,
deletion of which is recurrently identified in cancer[72]. Over the
past decades, it has become clear that aberrantly expressed miRNAs contribute
to the initiation or progression of human cancers[73]. Moreover,
emerging evidence demonstrated that miRNAs can function as oncogenes or tumor
suppressors[74].
MicroRNA expression and radiation
MiRNAs as critical gene regulators can influence
signaling pathways that alter multiple cellular processes, including the DNA
damage response(DDR) after IR. Increasing evidence demonstrates that the
expression levels of miRNAs significantly change after IR, which suggests that
miRNA play important roles in the IR-caused DDR[75]. While changes
in expression profiles of miRNA have been observed following irradiation in
mouse and human cells[76,77], the first evidence for functional
importance of a miRNA in radiation responses was shown in Drosophila[78].
Following irradiation of fly larvae, the bantam miRNA was shown to be
up-regulated. This miRNA in turn was shown to bind to the 3'-UTR of the
pro-apoptotic gene and affect its post-transcriptional down-regulation. This
miRNA-mediated gene repression resulted in decreased apoptosis induced by
radiation and increased larvae survival. In mouse embryonic stem cells, a group
of miRNA and their putative gene targets that are potentially involved in
response to DNA damage, were identified post-irradiation[76].
In whole body irradiated mice, the spleen and thymus tissues showed
sex-specific deregulation of miRNA expression. Among these, miRNA-34a (miR-34a)
and miR-7 were thought to be involved in counteracting radiation induced
hypomethylation[79]. MiR-709 target the Brother of the Regulator of
Imprinted Sites (BORIS), an important regulator of DNA methylation and
imprinting[80]. This study showed that the radiation induced DNA
damage resulted in increased miR-709 expression in exposed testes and decreased
levels of BORIS prevent massive aberrant erasure of DNA methylation, resulted
in downregulation of miRNA levels.
MiR-421 in neuroblastoma and HeLa cells downregulates ATM kinase, which
is a crucial integrator of DNA DSBs repair machinery. Ectopic expression of
miR-421 leads to S-phase cell cycle checkpoint changes and an increase in
radiosensitivity[81]. Recently, more miRNAs, including miR-18a,
miR-100, miR-101, miR-181, have been identified as novel regulators to control
the protein level of ATM[82-85]. BRCA1, a critical tumor suppressor,
is also recruited to DNA damage lesions, in which it facilitates DNA repair.
The level of BRCA1 is regulated by miR-182, miR-146a, and 146b-5p and may
impact breast cancer therapy and by defering from homologous recombination[86,87].
MiR-18a attenuates cellular repair of DNA double-strand breaks by directly
suppressing ATM. Ectopic expression of miR-18a significantly inhibited the
repair of DNA damage induced by etoposide, leading to accumulation of DNA
damage, increase in cell apoptosis and poor clonogenic survival[88].
Overexpression of miR-24, the first miRNA found to target H2AX, down-regulates
the level of H2AX, resulting in higher sensitivity of cells to IR[89].
Alternatively, the expression of miR-101 and miR-34a downregulated DNA-PKcs and
p53 binding protein1, respectively, impeding the NHEJ repair pathway[84,90].
The tumor suppressor p53 has a central role in the activation of genes in
multiple pathways, including cell-cycle regulation, tumor suppression, and
apoptosis. miR-125b and miR-504 have been identified as negative regulators of
p53 in several types of human cells[91,92]. Interestingly, miR-605,
and miR-143/miR-145 are post-transcriptionally activated by p53 and,
subsequently, target Mdm2, leading to rapid accumulation of p53[93,94].
Radiation treatment downregulate the levels of miR-521 and upregulate DNA
repair protein Cockayne syndrome protein A (CSA). Similarly, ectopic inhibition
of miR-521 results in increased CSA protein levels and plays an important role
in the radiosensitivity of prostate cancer cell lines[95]. Other
miRNAs, such as miR-34, miR-21, have been shown to regulate the expression of
important DDR network proteins BCL2, manganese superoxide dismutase (MnSOD),
and MSH2, respectively[96,97]. Following gamma-irradiation of human
lung carcinoma A549 and human B lymphoblastic cells IM9, a number of miRNA
showed more than 2-fold changes in irradiated cells[98,99]. The
target genes were involved in apoptosis, regulation of cell cycle, and DNA
damage and repair. A study involving gamma-irradiation of human B lymphoblast
cell lines showed dose-dependent changes in miRNA expression[100].
Low dose X-rays irradiated cells (0.05 Gy) demonstrated a decrease in
miR-20 and miR-21[101]. MiR-20 and miR-21 also increase in
tumorigenesis and miR-21 is considered as an onco-miRNA. In high dose
irradiated cells (10 Gy), miR-197 is upregulated. Carcinogenic characteristics
are observed in normal cells following injection of miR-197, suggesting that
stimulation of expression of miR197 by high dose radiation can lead to the
progression of tumorigenesis. In addition, ionizing radiation-induced oxidative
stress has been shown to play a role in altering miRNA expression[101].
The role of miRNA in the immune system and in inflammation has been reviewed in
the literature[102,103]. The mechanism of epigenetic regulation in
vivo is thought to be linked to inflammatory processes in the radiation
response. Therefore, these miRNA play important roles in the initiation and/or
perpetuation[104].
In vitro three-dimensional (3D) growth of tumors is a cell
culture model that more closely mimics the features of the in vivo environment
and is being used increasingly in the field of biological and medical research[105].
It has been demonstrated that cancer cells cultured in 3D matrices are more
radio-resistant compared to cells in monolayers[106]. However, the
mechanisms causing this difference remain unclear. Our experimental results
showed that more miRNAs were down regulated in three dimensional (3D) cultured
human lung epithelial cells (HBED-3KT), compared to the two dimensional (2D)
cultured HBEC-3KT cells after X-ray irradiation and carbon-beam irradiation as
well. The significantly different expression of miRNAs such as miR-1202,
miR-1290, miR-205 may be crucial in inhibiting the expression of target
proteins and, therefor, lead to the different cellular response in 2D and 3D
cultured cells[107].
Together, these studies suggest that radiation exposure alters miRNA
profiles in a way that can affect oxidative stress, DNA damage, DNA repair,
regulation of cell cycle, apoptosis, tumorigenesis and changes in DNA
methylation. MiRNA serve as integrators of the cellular response to ROS and DNA
strand breaks, both of them are results of ionizing radiation. Further
investigation of miRNA impact on cellular sensitivity to DNA-damaging agents
will be in favor of cancer therapy.
Conclusion and perspective
Based on above mentioned, we think that radiation
exposure can induce epigenetic changes including alterations in DNA
methylation, chromatin remodelling and miRNA expression. Epigenetic changes are
linked to alterations in global, repeat element and tumour suppressor promoter
methylation. Radiation exposure can induce relaxed heterochromatin
organisation. At low doses radiation, miRNA changes are involved in suppressing
radiation-induced apoptosis, stimulating DNA repair, counteracting
radiation-induced damage, and suppressing the progression of cancer but higher
doses of radiation lead to tumorigenic progression. However, some mechanisms
underlying the radiation-induced cellular response such as genomic instability
still remains largely unknown. The evidence presented in this review supports
that epigenetic mechanisms may be involved in. Induction of epigenetic changes
may be an initiating factor in the instability. These changes are heritable and
persist in the progeny of the irradiated cells. Additionally or alternatively,
epigenetic alterations may be a late arising delayed effect of irradiation
driving the perpetuation of the cellular response. Epigenetic regulation has
recently been established as an emerging tool of cancer therapy. Therefore, the
understanding of the epigenetic mechanism in cancer and radiation-induced
cellular response is required for the development of cancer radiotherapy. It is
also imperative to investigate more precise mechanisms involving in specific
gene or protein in order to better control carcinogenesis or prevent human from
radiation risk.
Acknowledgements
The work was supported by the National Nature Science
Foundation of China to BH [31170803, U1432121], and the National Key Scientific
Instrument and Equipment Development Project of China to BH [2012YQ03014210].
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Peer reviewers: An M Aerts, PhD,
SCK•CEN, Environment, Health and Safety, Molecular and Cellular Biology,
Radiobiology Unit, Boeretang 200, B-2400 Mol, Belgium; Wei Yang, Associate
Professor, Department of Radiobiology, School of Radiological Medicine and
Protection, Soochow University, Jiangsu province, China.
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