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DNA Methylation and Nonsmall Cell Lung Cancer.

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THE ANATOMICAL RECORD 294:1787–1795 (2011)
DNA Methylation and Nonsmall Cell
Lung Cancer
Soochow University Laboratory of Cancer Molecular Genetics,
Medical College of Soochow University, Suzhou, Jiangsu Province, People’s Republic of China
Lung cancer is the leading cause of cancer-related death in men and
women worldwide. Owing to the scarcity of effective tools for early detection and therapy strategies, the 5-year survival rate of lung cancer is
very poor. Because the accumulation of multiple genetic and/or epigenetic
changes, including DNA methylation, has been suggested to contribute to
development and progression of human cancers, improved understanding
of the relationship between DNA methylation and lung cancer will provide new insights for identifying promising biomarkers for diagnosis,
prognosis, and treatment of lung cancer. Here, we present a relatively
comprehensive review of DNA methylation and lung cancer, discuss DNA
methylation changes in carcinogenesis and metastasis of lung cancer, and
explore the association of microRNA with DNA methylation. Additionally,
we outline the applications of DNA methylation in clinical practice, such
as diagnosis, prognosis, and therapy of lung cancer. Anat Rec, 294:1787–
C 2011 Wiley-Liss, Inc.
1795, 2011. V
Key words: DNA methylation; lung cancer; hypermethylation;
hypomethylation; microRNA; diagnostics; prognostics;
Lung cancer, caused by cigarette smoking in 80%–90%
of cases (Hammond and Seidman, 1980), contributes to
the most frequent cancer-related mortality in men and
women worldwide (Molina et al., 2008). Despite the fact
that smoking is a high attributable risk to lung cancer,
20% of lifetime smokers develop the disease (Peto
et al., 2000), indicating that genetic susceptibility plays
a causal role in lung carcinogenesis. Lung carcinoma is
clinically divided into two broad groups, that is, small
cell lung cancer (SCLC) and nonsmall cell lung cancer
(NSCLC; Pfeifer and Rauch, 2009). NSCLC is the most
common type of lung cancer, accounting for 85% of all
lung cancer cases and consisting mainly of adenocarcinoma, squamous cell carcinoma (SCC), and large-cell
carcinoma (Liu et al., 2010).
Surgical resection is usually the most effective therapy
strategy for NSCLC patients. To a less extent, even if
the tumor is surgically resected, lung cancer patients
are still at high risk for recurrence and death. The overall 5-year survival rate of lung cancer is dismal with
merely <15% in all developed countries and 5% in developing countries (McWilliams et al., 2002), which is
mainly due to the scarcity of effective tools for early
detection and therapy strategies (Pfeifer and Rauch,
2009). Consequently, developing molecular markers for
early detection, predicting prognosis, and exploiting new
therapy agents of lung cancer are urgently needed.
Grant sponsor: National Natural Science Foundation of China;
Grant numbers: 81171894, 30973425, 30672400 (to H.-T. Zhang);
Grant sponsor: Program for New Century Excellent Talents in
University; Grant number: NCET-09-0165 (to H.-T. Zhang); Grant
sponsor: Science and Technology Committee of Jiangsu Province;
Grant number: BK2008162 (to H.-T. Zhang); Grant sponsor: SRF
for ROCS, State Education Ministry; Grant number: 2008890 (to
H.-T. Zhang); Grant sponsor: Qing-Lan Project of Education
Bureau of Jiangsu Province; Grant sponsor: ‘‘333’’ Project of
Jiangsu Province Government; Grant sponsor: Soochow Scholar
Project of Soochow University (to H.-T. Zhang).
*Correspondence to: Hong-Tao Zhang, Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow
University, 199 Ren’ai Road, Sino-Singapore Industrial Park, Suzhou 215123, People’s Republic of China. Fax: þ86-512-65882809.
Received 11 June 2011; Accepted 22 July 2011
DOI 10.1002/ar.21471
Published online 28 September 2011 in Wiley Online Library
As lung cancer could result from the accumulation of
multiple genetic and/or epigenetic changes, including
DNA methylation, more interests have been attracted to
the potential applications of DNA methylation in lung
cancer. Improved understanding of the relationship
between DNA methylation and lung cancer will provide
an exciting new era for identifying promising biomarkers
for diagnosis, prognosis, and treatment of lung cancer.
Epigenetic alterations, which result in aberrant gene
expression without any concomitant change in DNA
sequence, are heritable through cell division (Boumber
and Issa, 2011). They have been shown to play important roles in determining when and where as well as
whether a gene would express or silence. Thus far, DNA
methylation is considered as the best-characterized and
most easily quantifiable epigenetic mechanism underlying gene expression or silencing. In mammals, DNA
methylation occurs by transfer of a methyl group from a
donor S-adenosyl-methionine to the 5 position of cytosine
in the dinucleotide sequence CpG (Kerr et al., 2007).
DNA methylation can be completed by catalyze of DNA
methyltransferases, including DNA methyltransferase 1
(DNMT1), DNMT3A, and DNMT3B. Of them, DNMT1 is
responsible for maintaining pre-existing DNA methylation patterns in a cell (Jurkowska et al., 2011). DNA
methylation frequently occurs in CpG islands (CGIs)
around the 50 untranslated regions (50 -UTR) of genes
(Sekido et al., 1998). In detail, CGIs, close to transcriptional start sites and included in the first exon and
intron of a gene (Bird, 1986), are GC-rich (60–70%, CpG/
GpC>0.6). CGIs usually range from 0.5 to 5 kb and
occur per 100 kb on average (Belinsky et al., 2003).
These CGIs are present in nearly 50% of total genes and
are always promoter associated (Suzuki and Bird, 2008).
They play significant roles in protecting normal cells
from methylation, promoting expression of several key
genes involving cell growth and development, and
excepting for genes on the inactive X chromosome and
imprinted genes. Methylation of promoter region with
CGIs will result in inactivation of gene expression (Ushijima and Okochi-Takada, 2005). With respect to how
DNA methylation regulates gene expression, several possible theoretical ways are presented as follows: A possibility is that the methylated CpG residues could
interfere directly with the transcriptional factors that
can bind to the specific DNA sequence. Second, specific
repression factors, including MeCP1 and MeCP2, may
directly bind to methylated DNA. Third, active chromatin structure could be converted into an inactive form by
methylation. Lastly, epigenetic events can interact with
several cell cycle regulators (Chuang et al., 1997).
Deregulated gene expression via DNA methylation has
also been recognized as a key factor of aging (Qureshi
and Mehler,in press) and many kinds of pathologies (Shi
et al., 2007). To date, DNA methylation is emerging as
functions in not only cancer but also neurological, cardiovascular (Frey, 2005), and immunological diseases (Shi
et al., 2007; Esteller, 2006). In the following sections, we
will discuss what is known about DNA methylation
changes in lung cancer and how these alterations are
applied potentially to diagnosis and prognosis of the
Cancer, a multistep process disease characterized by
the accumulation of a series of molecular genetic and
epigenetic alternations, which generally exhibit genomewide hypomethylation and gene-specific hypermethylation
of DNA that is associated with silencing of gene expression (Esteller, 2007). Methylated DNA is accompanied by
condensed heterochromatin that is transcriptionally
incompetent, while unmethylated DNA is accompanied by
competent chromatin that is open to transcription. DNA
methylation status significantly alters in tumors when
compared with those in normal cells and is considered to
contribute to tumorigenesis (Suzuki et al., 2002). Furthermore, CpG methylation density is very important due to a
fact that low-density CpG methylation would merely
repress a weak promoter, while high-density methylation
is required for inhibition of a strong promoter (Bird,
1992). Global hypomethylation (Esteller and Herman,
2002) and regional promoter CGIs hypomethylation
(Chilukamarri et al., 2007; Lin et al., 2007b; Kim et al.,
2008) may activate proto-oncogenes, loss gene imprinting,
and reactivate transposable elements. Nevertheless,
hypermethylated CGIs may suppress the expression of
genes that contribute to tumor suppression, chromatin
condensation, and DNA repair (Baylin, 2005). There is
accumulating evidence demonstrating that aberrant
methylation of the promoter regions of multiple genes is
a common phenomenon in cancer (Baylin et al., 2001),
particularly, it occurs at the early stage during the
pathogenesis of lung carcinoma (Suzuki and Yoshino,
2010). Numerous reports have shown that there are conspicuous epigenetic alterations in carcinoma, giving rise
to phenotypic alternations combined with genetic changes,
and underlie lung tumorigenesis (Costello et al., 2000;
Esteller et al., 2001; Feinberg, 2004; Wilson et al., 2006).
DNA hypermethylation, a well-known epigenetic alteration at CGIs, is considered as a major mechanism
underlying loss of gene expression. DNA hypermethylation generally contributes to negative regulation of cell
growth in large amount of ways, and its relationship
with the transcriptional silencing of genes has been
largely recognized (Bird and Wolffe, 1999; Rountree
et al., 2001; Wade, 2001). The silencing is mediated
through stabilizing the chromatin structure or inhibiting
the binding of transcription factors to response elements
harboring CpG sites (Costello et al., 2000). CGIs are
extensively hypermethylated in human cancers (Costello
et al., 2000; Esteller et al., 2001; Jones and Baylin,
2002), including lung cancer (Tsou et al., 2002; Digel
and Lubbert, 2005). Hundreds of genes, including p16,
RASSF1A, DAPK, MGMT, CDH13, CDH1, Adenomatous
Polyposis coli (APC), RARb, and so forth. (Virmani et al.,
2000; Heller et al., 2010), have been recognized to harbor dense methylation in promoter CGIs in lung cancer,
especially in NSCLC (Table 1). Among these potential
tumor suppressor genes (TSGs), RARb is methylated in
40–43% of NSCLC, p16 25–41%, DAPK 16–44%, MGMT
16–27%, and RASSF1A 30–40% (Zochbauer-Muller
et al., 2002; Belinsky, 2005). The following sections will
review the previous findings of DNA hypermethylation
in NSCLC, especially in the context of gene silencing.
Promoter hypermethylation-based silencing of p16,
located at 9p21 and encoding a cell cycle regulatory
TABLE 1. DNA methylation changes of several key genes and their roles in lung cancer
Methylation changes
Cell type
Belinsky (1998), Belinsky (2002)
Damman (2001), Honorio (2001),
Dammann (2005)
Brabender (2001)
Cell-cycle control
Ras signaling
Regulation of cell proliferation,
migration, and adhesion
Cell-cycle control
Inhibition of epithelial
cell growth
DNA repair
Regulation of cell adhesion
Cell-cycle regulation
Regulation of cell differentiation
and proliferation
Regulation of cell motility
and cell adhesion
DNA repair
Cell-cycle regulation
Ohtani-Fujita (1993),
Joseph (2004)
Zhang (2004)
Zochbauer-Muller (2001)
Belinsky (2005)
Toyooka (2001)
Toyooka (2001)
Virmani (2000)
Zochbauer-Muller (2001)
Zochbauer-Muller (2001)
Kuroki (2003)
Lung cancer
Liu (2008)
Liu (2008)
Jang (2001)
Liu (2005)
P16, cyclin-dependent kinase inhibitor 2A; RASSF1A, Ras association domain family member 1; APC, adenomatous polyposis coli; RB, retinoblastoma; TGFBR2, transforming growth factor beta receptor II; DAPK, death associated protein kinase; MGMT, O-6-methylguanine-DNA methyltransferase; CDH13, cadherin 13; CDH1, cadherin 1; RARb, retinoic acid
receptor beta; FHIT, fragile histidine triad gene; GSTP1, glutathione S-transferase pi 1; SEMA3B, semaphorin 3B;
hOGG1, 8-oxoguanine DNA glycosylase; MAGE, melanoma antigen family A, 1; SNCG, gamma-synuclein.
protein (Gopisetty et al., 2006), is always observed in
lung cancer (Auerkari, 2006) and plays an important
role in preventing cyclin-dependent kinases 4 (CDK4)
and CDK6 from forming an active complex with cyclin D
in early stage of lung cancer and increasing consistently
with cancer deterioration (Belinsky et al., 1998, 2002).
RASSF1A promoter is frequently hypermethylated in a
variety of cancers, including lung carcinoma (Dammann
et al., 2000, 2001, 2005; Honorio et al., 2001), and its hypermethylation leads to epigenetic silencing of RASSF1A
by HOXB3-mediated induction of DNMT3B expression
(Palakurthy et al., 2009). APC is a negative regulator of
Wingless-INT (WNT) pathway, which involves in selfrenewal of stem cell (Mazieres et al., 2005), and APC
methylation occurrence rate is up to 94% in NSCLC but
20% in normal control group (Brabender et al., 2001).
Activation of the WNT pathway is in part attributed to
methylation-based silencing of APC in lung cancer
(Toyooka et al., 2004b; Tsou et al., 2005). In contrast,
nine out of 11 noncancerous lung specimens presented
low levels of APC methylation (Kerr et al., 2007). Methylation-mediated blocking of activation of RB promoter
may reduce RB expression to 8.0% in vitro (OhtaniFujita et al., 1993). CGIs at 50 end of the RB gene were
found hypermethylated in NSCLC (Joseph et al., 2004).
Aberrant methylation of TGFBR2, a major inhibitor of
epithelial cell growth and functions as TSG, may be
associated with down-regulation of TGFBR2 expression
at the transcriptional level in NSCLC (Zhang et al.,
2004). Although TGFBR1 haplotype was reported to associate with NSCLC risk (Lei et al., 2009), no aberrant
DNA methylation was found to correlate with defective
expression of TGFBR1 in NSCLC (Zhao et al., 2008).
Apart from the function of DNA methylation in carcino-
genesis, it is possible that the inactivation of metastasis
suppressor gene, such as CDH11 (Kashima et al., 2003),
could play an important role in pulmonary metastasis.
Besides the genes described above, there are many genes
presenting aberrant methylation in lung cancer, including FHIT, GSTP1, hOGG1, SEMA3B, and BLU (Table 1;
Zochbauer-Muller et al., 2001; Liu et al., 2008).
Taken together, much data support the notion that
methylation of specific genes occurs merely in lung cancers but not at all or only in an extremely low proportion
of the corresponding noncancerous lung tissues (Toyooka
et al., 2001; Zochbauer-Muller et al., 2001; Heller et al.,
2006). Most methylation studies focus mainly on NSCLC
but few on SCLC, therefore more methylation information on SCLC needs to be gathered in the future.
With respect to large amounts of studies showing hypermethylation in lung cancer, it reminds us the issue of
whether there is discovery for demethylation of CGIs.
Although it occurs much less frequently than hypermethylation, gene-specific hypomethylation has been
observed in human cancer (Esteller et al., 2001).
Gene-specific hypomethylation occurs at CpG sites in
promoters of specific genes, leading to increased expression of growth factors, proto-oncogenes, genes that are
involved in cancer cell proliferation, and invasion and
metastasis (Szyf et al., 2004). For instance, hypomethylation enhances expression of uPA, which serves as urokinase type plasminogen activator in tumor cells that
could degrade extracellular matrix (Werb, 1997; Andreasen et al., 2000). Expression of the MAGE gene was
found in 70–85% of NSCLC, and its activation was associated with loss of methylation in 75–80% of tumors
(Jang et al., 2001). Hypomethylation of the synucleingamma gene is associated with the metastatic potential
of various human cancers, including lung carcinoma
(Liu et al., 2005). Re-expression of tumor antigens may
contribute to cancer metastasis in multiple ways, including hypomethylation (Simpson et al., 2005).
In addition to gene-specific hypomethylation, global
hypomethylation was reported to bring about genomic
instability that may in turn accelerate secondary genetic
changes (Eden et al., 2003; Gaudet et al., 2003). DNA
short tandem repeats alternation that caused by microsatellite instability has been observed in 22% of NSCLC
and 35% of SCLC (Mao, 2001). It is supposed that hypomethylation could induce genomic instability either by
chromosomal rearrangement or by transposable elements reactivation (Roman-Gomez et al., 2005; Yamada
et al., 2005; Howard et al., 2008). Genomic hypomethylation occurs specifically at transposable elements and repetitive sequences such as long interspersed nuclear
element (LINE), short interspersed nuclear element, and
long terminal repeat elements, subtelomeric regions and
segmental duplications. Repetitive DNA elements are
usually hypomethylated in lung SCCs (Pfeifer and
Rauch, 2009). For example, the percentage of hypomethylation at LINE-1 repeat sequences in several types of
cancer, including lung cancer, is higher than that in normal tissues (Chalitchagorn et al., 2004). Furthermore,
unless altering the levels of gene expression, genomic
hypomethylation may facilitate the gain and loss of several chromosomes, which could result in genomic instability that causes development and progression of cancer
(Sulewska et al., 2007). But the mechanisms underlying
cancer-related DNA hypomethylation of repetitive DNA
elements are not yet fully understood. One supposed
mechanism is that reactivation of a DNA demethylase
that is normally not expressed in adult human cells may
make CpG methylation of repetitive DNA sequence lost
in tumor cells. Another possible mechanism by which
small-RNA could regulate methylation of repetitive DNA
sequence is through heterochromatin formation.
MicroRNAs (miRNAs) are short noncoding RNA molecules with 22 nucleotides long and are found in
eukaryotic cells. MiRNA is considered as a novel epigenetic regulator of gene expression (Esquela-Kerscher
and Slack, 2006), playing important roles in various biological processes such as development, proliferation, cellular differentiation, and apoptosis through silencing
specific target genes (He and Hannon, 2004). They may
serve as negative regulators of gene expression by binding to complementary sequences in the 30 -UTR of target
mRNAs or by guiding mRNA degradation (Eulalio et al.,
2008). There is growing evidence indicating that miRNAs may function as TSGs or oncogenes as well (Calin
and Croce, 2006).
Although miRNAs, including Let-7 and miR-128b, are
found to aberrantly express in lung carcinoma, investigating expression patterns and functions of miRNAs in
lung cancer is just at the early stage. Let-7 is a wellunderstood example of miRNAs, and it is one of the first
identified miRNAs and seems to function in a critical
role as TSG in lung cancer (Takamizawa et al., 2004).
Indeed, over-expression of let-7 may result in various
biological processes, including inhibition of Ras protein
expression (Johnson et al., 2005) and repression of pro-
liferation of lung cancer cells (Johnson et al., 2007).
Additionally, over-expression of miR-206 can inhibit
migration and invasion of lung cancer cells (Wang et al.,
2011). As a direct negative regulator of the EGFR oncogene, miR-128b (located on chromosome 3p) expression
is lost in lung cancers (Weiss et al., 2008). Let-7a-3 and
miR-17-92, typical examples of oncogenic miRNAs, were
observed to up-regulate in lung cancer cells (Hayashita
et al., 2005; Volinia et al., 2006), could enhance cell
proliferation (Hayashita et al., 2005) and inhibit lung
epithelial progenitor cells differentiation in transgenic
mice (Matsubara et al., 2007).
Next, we will discuss the relationship between DNA
methylation and regulation of miRNAs expression in the
following two aspects (Fig. 1). First, it is worth noting
that aberrant DNA methylation is a mechanism for activation or silencing of the miRNA genes, including let-7a3 and miR-124a (Brueckner et al., 2007; Fazi et al.,
2007; Lujambio et al., 2007; Bueno et al., 2008). Hypomethylation of let-7a-3 may cause over-expression of let7a-3 in lung cancer cells, enhancing cancer phenotypes
and oncogenic alternations at the transcription level
(Brueckner et al., 2007). Hypermethylation of miR-124a
was identified to mediate Rb phosphorylation and CDK6
activation in lung ACs (Lujambio et al., 2007). Although
little is known about the accurate mechanisms underlying regulation of miRNAs expression in lung cancer, a
few existing literature indicates that DNA methylation
might affect the status of miRNAs. Second, it is great of
interest that miRNAs are regulators as well as targets
of DNA methylation. MiRNA-29 family may restore
aberrant methylation in lung caner by targeting 30 -UTR
of DNMT3A and DNMT3B, which are frequently upregulated in lung cancer and associated with poor prognosis (Fabbri et al., 2007). Increased expression of
miRNA-29 normalizes aberrant patterns of methylation
in NSCLC, induces re-expression of methylation-silenced
TSGs, such as FHIT and WWOX, and inhibits lung carcinogenesis (Fabbri et al., 2007).
Taken together, elucidating the association between
miRNAs and DNA methylation will provide an improved
understanding for development, progression, and novel
therapeutic targets of lung cancer.
As DNA methylation has been identified at early stage
of lung cancer, its potential usefulness as diagnostic or
prognostic biomarkers of the disease should be considered as well as its contribution to tumorigenesis. DNA
methylation of specific genes seems to be a powerful molecular marker for early detection, prognosis, disease recurrence, risk assessment, and monitoring response to
therapy of lung cancer.
There is rapidly increasing evidence supporting the
idea that DNA methylation would become clinically
potential molecular markers of cancer. It is understood
that the useful molecular marker should associate with
cancer development and needs to show not only significantly different between normal and tumor tissue but
Fig. 1. Schematic diagram of the relationship between DNA methylation and regulation of miRNAs
expression in lung cancer.
also significantly different specific and sensitive for neoplastic transformation. In this section, we will present a
brief summary of the previous reports, focusing on DNA
methylation that potentially acts as diagnostic biomarkers in preinvasive lung cancer. An exemplified
report is that p16 promoter hypermethylation is an early
event of lung tumorigenesis (Belinsky et al., 1998;
Nuovo et al., 1999). In the following investigation, Palmisano et al. (2000) demonstrated that aberrant methylation of p16 and/or MGMT promoters was detected in
100% of sputum DNA from patients with lung SCC up
to 3 years before clinical diagnosis. MGMT, a DNA
repair enzyme, is commonly inactivated via aberrant
promoter methylation in lung ACs (Pulling et al., 2003).
These data suggest that hypermethylation of p16 and
MGMT may become valuable biomarkers for early detection of lung carcinomas. More recently, Rauch et al.
(2008) identified 11 CGIs that were methylated in 80–
100% of lung SCC, and many hold promise as effective
biomarkers for early detection of lung cancer.
Why is DNA methylation a feasible marker to detect
lung cancer and superior to other diagnostic biomarkers?
First, DNA used for the methylation analysis is chemically more stable than proteins and RNA. Second, the
frequency for aberrant methylation of specific CGIs is
high in human cancer (Miyamoto et al., 2003). Third,
DNA methylation can be feasibly amplified and sensitively detected through PCR-based approaches, such as
methylation-specific PCR (Herman et al., 1996) and
quantitative methylation-specific PCR (Laird, 2003).
Fourth, as DNA hypermethylation generally occurs in or
near cancer-specific gene promoters, design of the targeted probes to measure this epigenetic change is convenient. Lastly, aberrant DNA methylation can be
identified in early stage of tumorigenesis and even in
non-neoplastic tissues (Miyamoto and Ushijima, 2005).
Although specificity and sensitivity of DNA methylation as diagnosis marker are various due to relatively
small case–control studies and nonstandard assays from
a majority of investigations, a series of candidate DNA
methylation markers will still provide promising
insights for early detection of lung cancer.
Conventionally, tumor properties, such as pathological
subtypes, nodal invasion, and metastasis, could roughly
predict outcomes of cancers, including lung cancer.
Besides these traditional prognostic factors, a wealth of
molecular biomarkers, including DNA methylation, may
offer refined information to the outcome of cancer and
thence guide the selection of specific therapies.
More recently, Brock et al. (2008) found aberrant patterns of promoter methylation of APC, RASSF1A, p16,
and CDH13 associated with early recurrence in Stage I
NSCLC. In support of this notion, Yamamoto et al.
(2009) indicated that synchronous methylation of
CDH13 and p16 is more effective as a prognostic biomarker than merely p16 methylation. Combining with
hypermethylated FHIT, methylation of p16 is related to
poorer prognosis of Stage I NSCLC (Kim et al., 2006).
Additionally, hypermethylation of the promoter regions
of 14-3-3r, a critical G2-M checkpoint control gene,
emerges as an effective prognosis biomarker of NSCLC
patients (Fu et al., 2000). The prognostic value of 14-33r methylation was evaluated in serum DNA from 115
cisplatin/gemcitabine-treated advanced NSCLC patients
(Ramirez et al., 2005), suggesting that methylation of
14-3-3r is a novel independent prognostic factor for survival in NSCLC patients receiving platinum-based
However, there are still conflicting results generating
on the relationship between methylation of specific genes
and lung cancer prognosis. For example, methylation of
RASSF1A was found to correlate with earlier recurrence
in Stages I and II NSCLC (Endoh et al., 2003), but no
association of RASSF1A methylation was confirmed by
other investigations (Toyooka et al., 2004a). Advancement
in DNA methylation-based prognosis assessment of lung
cancer has been limited to some extent, and more information about aberrant DNA methylation as prognosis
biomarker of the disease needs to be urgently elucidated.
Given the fact that epigenetic alternations that play
important roles in tumorigenesis and metastasis could
be reversed by the pharmacologic application, DNA
methylation represents new potential therapeutic targets for lung cancer. Reactivation of methylation-mediated silencing of specific genes in lung cancer would
cause a series of events, including growth arrest, cellular
differentiation and induction of apoptosis, and then
result in anticancer activity. Nowadays, inhibition of
DNA methylation will be of particular interest as anticancer therapy.
Over the past few years, investigators have seen that
DNA methylation may be effectively reversed by therapies or drugs, including both adenosine and nonadenosine classes DNMT inhibitors. The adenosine class
inhibitors consists of 5-aza-20 -deoxycytidine (5-Aza-CdR,
decitabine) and 5-azacytidine which can induce degradation of DNMTs through forming irreversible covalent
bonds with them, thus leading to DNA demethylation
and reactivation of hypermethylated genes. This kind of
drug has demonstrated an activity to promote anticancer
in leukemia but little activity in solid tumors (Goffin
and Eisenhauer, 2002). As a nonadenosine inhibitors,
MG98 is an antisense oligodeoxynucleotide directed
against the 30 -UTR of DNMT1 mRNA, and it has shown
an ability to inhibit DNMT1 expression without effecting
DNMT3 and to cause re-expression of p16 in bladder
and colon cancer cells (Goffin and Eisenhauer, 2002).
Antisense-mediated depletion of DNMT1 and DNMT3B
mediates caspase-dependent and p53-independent apoptosis in lung cancer lines, which is not attributable to
induction of TSGs, such as RASSF1A and p16 (Kassis
et al., 2006). These findings further support DNMT inhibition strategies for therapy of lung cancer. Indeed,
there is supporting evidence that a Stage IV NSCLC
patient after treatment with 5-Aza-CdR has long-term
survival (Momparler and Ayoub, 2001). Mithramysin-A
may decrease methylation of CGIs and inhibit NSCLC
invasion phenotype in vitro by reducing DNMT1 expression (Lin et al., 2007a). Although the anti-DNMTs
agents, including hydralazine, procainamide, zebularine,
procaine, and epigallocatechin-3-gallate, are clinically
measured for lung cancer patients, the preliminary outcome of them is not remarkable (Digel and Lubbert,
Until now, only a few preclinical trials have measured
the efficacy of DNMT inhibitors therapy. Decitabine was
observed to significantly restrain cancer development of
ApcMin mice and reduce intestinal adenomas formation
by 82% (Laird et al., 1995), and decitabine could inhibit
tumor formation of lung in mice treated with a tobaccospecific carcinogen (Lantry et al., 1999). These studies
provide a new era for lung cancer therapy with the use
of DNMT inhibitors.
Taken together, the improvements made in lung cancer epigenetics will facilitate development of drugs that
use DNA methylation as attractive therapeutic target.
DNMT inhibitors, such as decitabine and MithramysinA, are potential lung cancer therapy drugs that target
DNA methylation. Nevertheless, DNA methylation-based
therapy has its limitations in the treatment of lung cancer with the possibility of carcinogenicity and mutagenicity, as DNMT inhibitors could nonspecifically activate
oncogenic genes and transposable elements. Meanwhile,
there is a possibility that corrected methylation will
restore to the primary status based on its reversible
nature. Therefore, proper investigation designs and
independent experimental validation are warranted to
ensure the translation of them to the clinic.
There is sufficient evidence that DNA methylation is
an early event observed in the pathogenesis of lung cancer, suggesting that DNA methylation may become feasible markers for diagnosis, prognosis, and potential
targets of therapy. Although there are obviously encouraging results obtained in this field, lots of challenges
still lie ahead. First, the exact contribution of aberrant
DNA methylation to lung cancer etiology is not well
known. Second, the mechanisms underlying cancer-specific methylation alternation remain to be clarified.
Third, more investigations on mouse models of epigenetic alterations will be moving toward, and to some
extent elucidate the causative significance of DNA methylation in initiating lung carcinoma. Additionally, it will
be of importance to identify the DNA-methylated genes
that undoubtedly contribute to development and progression of lung cancer. Lastly, integrating DNA methylation-based strategies with conventional management of
lung cancer will be clinically needed.
Although DNA methylation markers have great potential to become specific and sensitive diagnostic tools for
early detection of lung cancer, further preclinical trials
are needed before the promising DNA methylation
markers are introduced into conventional clinical diagnosis. Developing sensitive and reliable techniques that
can detect rare methylated DNA molecules in serum,
sputum, and circulating tumor cells will be a top priority
in the future. DNA methylation may also offer novel
promising indicators for prognosis and treatment that
monitor recurrence and response to therapy of lung
In conclusion, although we are still at the very beginning of elucidating the mechanisms of DNA methylation
changes in lung cancer and of practicing the translation
of it to the clinic, much information on the aberrant
DNA methylation has been so far obtained. Therefore, it
provides support for the idea that novel methylationbased therapies will clinically cure lung cancer one day.
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