Clin Genet 2012: 81: 303–311 © 2011 John Wiley & Sons A/S

Printed in Singapore. All rights reserved CLINICAL GENETICS

doi: 10.1111/j.1399-0004.2011.01809.x

Review

Epigenetic modifications in cancer

Kanwal R, Gupta S. Epigenetic modifications in cancer. R Kanwala and S Guptaa,b,c

Clin Genet 2012: 81: 303–311. © John Wiley & Sons A/S, 2011 a Department of Urology, Case Western
Reserve University, b Department of
Cancer initiation and progression is controlled by both genetic and
Urology, University Hospitals Case
epigenetic events. The complexity of carcinogenesis cannot be accounted Medical Center, and c Department of
for by genetic alterations alone but also involves epigenetic changes. Urology, Case Comprehensive Cancer
Epigenetics refers to the study of mechanisms that alter gene expression Center, Cleveland, OH, USA
without altering the primary DNA sequence. Epigenetic mechanisms are
heritable and reversible, and include changes in DNA methylation, histone
modifications and small noncoding microRNAs (miRNA). Disruption of
epigenetic processes can lead to altered gene function and malignant Key words: cancer – DNA methylation –
cellular transformation. Aberrant epigenetic modifications probably occur epigenetics – histone modification –
at a very early stage in neoplastic development, and they are widely microRNA
described as essential players in cancer progression. Recent advances in Corresponding author: Sanjay Gupta,
epigenetics offer a better understanding of the underlying mechanism(s) of PhD, Department of Urology, Case
carcinogenesis and provide insight into the discovery of putative cancer Western Reserve University, University
biomarkers for early detection, disease monitoring, prognosis, and risk Hospitals Case Medical Center, 10900
assessment. In this review, we summarize the current literature on Euclid Avenue, Cleveland, Ohio 44106,
epigenetic changes causing genetic alterations that are thought to contribute USA.
to cancer, and discuss the potential impact of epigenetics future research. Tel.: (216) 368 6162;
fax: (216) 368 0213;
Conflict of interest e-mail: [email protected]

Nothing to declare. Received 18 October 2011, revised and

accepted for publication 10 November
2011

Cancer, initially recognized as a genetic disease, imprinting, transcriptional regulation, and developmen-
is now known to involve epigenetic abnormalities tal processes (5). DNA methylation usually takes place
along with genetic alterations. It is becoming clear at the 5 position of the cytosine ring within CpG
that microenvironment-mediated epigenetic perturba- dinucleotides, and its consequence is the silencing of
tions play an important roles in the development of genes and noncoding genomic regions. The modifi-
neoplasia (1). Epigenetics refers to the study of heri- cation at 5-methyl cytosine is catalyzed by enzyme
table changes in gene expression that occur without a DNA methyltransferases (DNMTs) (6). There are three
change in DNA sequence which are sufficiently power- main DNMTs: DNMT1, which maintains the existing
ful to regulate the dynamics of gene expression (2). The methylation patterns following DNA replication, and
key processes responsible for epigenetic regulation are DNMT3A and DNMT3B, de novo enzymes that tar-
DNA methylation, histone modifications and posttran- get unmethylated CpGs to initiate methylation and are
scriptional gene regulation by noncoding RNA com- highly expressed during embryogenesis and minimally
monly referred as microRNAs (3). These mechanisms expressed in adult tissues (7). Another family mem-
are critical components in the normal development and ber is DNMT-3L that lacks intrinsic methyltransferase
growth of cells and their modifications contribute to activity; it interacts with DNMT3a and 3b to facilitate
neoplastic phenotypes (4). methylation of retrotransposons (8). Both the establish-
ment and maintenance of DNA methylation patterns are
critical for development as mice deficient in DNMT3B
DNA methylation
or DNMT1 are embryonic lethal and DNMT3A-null
In eukaryotes, methylation is characterized by epi- mice die by 4 weeks of age (9). In normal cells,
genetic DNA modifications which play an important DNA methylation occurs predominantly in repetitive
role in maintenance of genome integrity, genomic genomic regions, including satellite DNA and parasitic

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Kanwal and Gupta
elements such as long interspersed transposable ele- methylation binding protein MBD2, which directs the
ments (LINEs) and short interspersed transposable ele- NuRD complex to methylate DNA (14, 15). These and
ments (SINEs), maintaining genomic integrity (10). other recent findings have established that DNA cyto-
Methylated cytosines account for approximately 1% sine methylation is a critical component of epigenetic
of total nucleotides and about 75% of all CpG dinu- gene regulation. A list of DNA methylation genes dis-
cleotides in the human genome. The CpG dinucleotides rupted in various human cancers is shown in Table 1.
are unevenly distributed across the human genome, but
are concentrated in dense pockets called CpG islands
(CGIs). About 50–60% of gene promoters lie within Histone modification
CpG islands, and it is estimated that the human genome Histone modifications influence chromatin structure
contains approximately 29,000 CpG sequences (11). which plays an important role in gene regulation and
CpG islands particularly those associated with pro- carcinogenesis (16). Chromatin is a highly ordered
moters are generally unmethylated in normal cells, structure consisting of repeats of nucleosomes con-
providing access to transcription factors and chromatin- nected by linker DNA. Each nucleosome encompasses
associated proteins for the expression of most house- ∼146 bp of DNA wrapped around an octamer of
keeping genes and several other regulated genes histone proteins. These octamers consist of two sub-
although some of them (∼6%) become methylated units of each of the following core histone proteins:
in a tissue-specific manner during early development H2A, H2B, H3 and H4 (17). Chromatin consists of
or in differentiated tissues (4, 12). DNA methylation DNA, histones, and non-histone proteins condensed
can inhibit gene expression directly, by inhibiting the into nucleoprotein complexes and functions as the phys-
binding of specific transcription factors, and indirectly, iological template of all eukaryotic genetic informa-
by recruiting methyl-CpG-binding domain (MBD) pro- tion (18). Histones are small basic proteins containing
teins. The associated MBD family members in turn a globular domain and a flexible charged NH2 termi-
recruit histone-modifying and chromatin-remodeling nus known as the histone tail, which protrudes from
complexes to methylated sites (13). To date, six methyl- the nucleosome. Regulation of gene expression occurs
CpG-binding proteins, including methylcytosine bind- through posttranslational modifications of the histone
ing protein 2 (MECP2), MBD1, MBD2, MBD3, MBD4 tails provided by covalent modifications including
and Kaiso, have been identified in mammals. MECP2 acetylation, methylation, phosphorylation, ubiquitina-
binds methylated DNA in vitro and in vivo. It contains tion, sumoylation, proline isomerization, and ADP
a MBD at its amino terminus and a transcription repres- ribosylation (19–21). Posttranslational modifications to
sion domain (TRD) in the middle (13). Furthermore, it histone tails govern the structural status of chromatin
has been shown that nucleosome remodeling complex and the resulting transcriptional status of genes within
(NuRD) can methylate DNA by interacting with DNA a particular locus. These modifications are reversible

Table 1. DNA methylation gene changes in various human cancers

DNA
methyltransferase Function Alterations Cancer type

DNMT 1 Maintenance of methylation, repression of Upregulation, mutation Colorectal cancer, ovarian cancer
transcription
DNMT3a De novo methylation during Upregulation Colorectal cancer, breast cancer,
embryogenesis, imprint establishment, ovarian cancer, esophageal
repression squamous cell carcinoma
DNMT3b De novo methylation during Upregulation Breast cancer, hepatocellular
embryogenesis, repeat methylation carcinoma, colorectal cancer,
repression
DNMT3L Interacts with DNMT3a &b and facilitate Upregulation
methylation
Methyl-CpG-
binding proteins
MeCP2 Transcription repression Upregulation, Mutation Prostate cancer, Rett syndrome,
MBD1 Transcription repression Upregulation, Mutation Prostate cancer, colon cancer, lung
cancer
MBD2 Transcription repression Upregulation, Mutation Prostate cancer, colon cancer, lung
cancer
MBD3 Transcription repression Upregulation, Mutation Colon cancer, lung cancer
MBD4 DNA repair, glycosylase domain, repair of Upregulation, Mutation Colon cancer, gastric cancer,
deaminated 5-methylC endometrial cancer
Kaiso Transcription repression Upregulation Colon, intestinal, lung cancer

DNMT, DNA methyltransferase; MBD, methyl-CpG-binding domain.

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Epigenetics and cancer
and are controlled by a group of enzymes includ- Epigenetic modifications in cancer
ing histone acetyltransferases (HATs) and deacetylases
In human cancers, aberrant epigenomics are known to
(HDACs), methyltransferases (HMTs) and demethy-
contribute to various phases of neoplastic development
lases (HDMs), kinases, phosphatases, ubiquitin lig-
ases and deubiquitinases, SUMO ligases and proteases including initiation, promotion, invasion, metastases
which add and remove such modifications (20, 22). and chemotherapy resistance. It has been proposed
Chromatin is divided into two distinct conformation recently that more than 300 genes and gene prod-
states: heterochromatin, which is densely compacted ucts are epigenetically altered in various human can-
and transcriptionally inert and euchromatin, which cers (4). A link between DNA methylation and cancer
is decondensed and transcriptionally active (17, 23). was first shown in 1983, when it was shown that
Euchromatin is characterized by high levels of acety- the genomes of cancer cells are hypomethylated rel-
lation and trimethylated H3K4, H3K36 and H3K79. ative to their normal counterparts (29). In terms of
On the other hand, heterochromatin is characterized DNA methylation, cancer cells show genome-wide
by low levels of acetylation and high levels of H3K9, hypomethylation and site-specific CpG island pro-
H3K27 and H4K20 methylation (12, 24, 25). Studies moter hypermethylation (30, 31). Hypermethylation
have shown that histone modification levels are predic- at specific genes typically affects promoter CpG-
tive for gene expression. Actively transcribed genes are islands inactivating transcription. Hypermethylation is
characterized by high levels of H3K4me3, H3K27ac, observed at specific CpG islands. The transcriptional
H2BK5-azacytidine (H2BK5ac) and H4K20me1 in the inactivation caused by promoter hypermethylation
promoter and H3K79me1 and H4K20me1 along the affects genes involved in the main cellular pathways:
gene body (26). Genome-wide studies have revealed DNA repair [hMLH1 (mismatch repair gene 1),
that various combinations of histone modifications in MGMT (O6-methylguanine–DNA methyltransferase),
a specific genomic region can lead to a more ‘open’ or WRN (Werner syndrome, RecQ helikase like), BRCA1
‘closed’ chromatin structure resulting in the activation (breast cancer 1)], cell cycle control (p16 INK4a ,
or repression of gene expression (12, 24, 25). A list of p15 I NK4b , RB ), Ras signaling {RASSF1A [Ras asso-
the histone-modifying genes altered during carcinogen- ciation (RalGDS/AF-6) domain family member 1],
esis is presented in Table 2. NOREIA}, apoptosis [TMS1 ( target of methylation-
induced silencing 1), DAPK1 (death-associated pro-
tein kinase), WIF-1, SFRP1 ], metastasis [cadherin 1
Noncoding RNAs (CDH1), CDH13, PCDH10 ], detoxification [GSTP1
MicroRNAs (miRNAs) are small ncRNAs of ∼22 (glutathione S-transferase pi 1)], hormone response
nucleotides and are involved in posttranslational gene (ESR1, ESR2 ), vitamin response [RARB2 (retinoic acid
silencing by controlling mRNA translation into pro- receptor b2), CRBP1] and p53 network [p14 ARF , p73
teins (27). miRNAs induce heritable changes in gene (also known as TP73 ), HIC-1 ] among others. This pro-
expression without altering DNA sequence and thus vides tumor cells with a growth advantage and increases
contribute to the epigenetic landscape. In addition, miR- their genetic instability and aggressiveness (22, 30).
NAs can both regulate and be regulated by other epige- Hypomethylation in tumor cells is primarily caused by
netic mechanisms (28). Although miRNA are vital to the loss of methylation from repetitive regions of the
normal cell physiology their mis-expression has been genome and the resulting genomic instability is a hall-
linked to several diseases, including cancer (4). Can- mark of tumor cells. In addition, imprinting patterns
cer development and miRNA profiles are now being are often disturbed (32). In cancers, hypomethylation
used to classify human cancers (23, 28, 27). Approxi- is often associated with oncogenes. c-Myc, a transcrip-
mately, 1000 miRNA genes have been computationally tion factor that acts as an oncogene, is one of the widely
predicted in the human genome with each miRNA tar- reported hypomethylated genes in cancers. Hypomethy-
geting multiple protein-coding transcripts. It has been lation at specific promoters can activate the aberrant
predicted that miRNAs regulate the translation rate of expression of oncogenes and induce loss of imprinting
more than 60% of protein-coding genes (7), and par- (LOI). The most common LOI event due to hypomethy-
ticipate in the regulation of cellular processes. Like lation is insulin-like growth factor 2 (IGF2 ), which has
mRNAs, miRNAs are mainly transcribed by RNA been reported in a wide range of tumor types, including
polymerase-II although miRNA synthesis is known to breast, liver, lung and colon cancer (33, 34). S100P in
occur by RNA polymerase-III in those miRNAs that pancreatic cancer, SNCG in breast and ovarian cancers
reside near tRNA, Alu and mammalian-wide inter- and melanoma-associated gene (MAGE ) and dipeptidyl
spersed sequences (28). The first identified miRNAs, peptidase 6 (DPP6 ) in melanomas are well-studied
the products of the Caenorhabditis elegans genes examples of hypomethylated genes in cancer (12, 35).
lin-4 and let-7, have important roles in controlling In addition to changes in DNA methylation, histone
developmental timing and probably act by regulating modification patterns are also altered in human tumors.
mRNA translation. When lin-4 or let-7 is inactivated, Recent studies have shown that histone modification
specific epithelial cells undergo additional cell divi- levels are predictive for gene expression. Actively
sions instead of their normal differentiation (27). A transcribed genes are characterized by high levels of
list of miRNAs dysregulated in cancer is presented in H3K4me3, H3K27ac, H2BK5ac and H4K20me1 in the
Table 3. promoter and H3K79me1 and H4K20me1 along the

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Kanwal and Gupta
Table 2. Histone modification genes altered in various human cancers

Histone deacetylases Alterations Cancer type

HDAC1 Upregulation/Downregulation Colorectal cancer, cervical dysplasias, endometrial

stromal sarcomas, gastric carcinomas, colon
cancer
HDAC2 Upregulation/Mutation Multiple gastric carcinomas, colon cancer
HDAC3 Upregulation Colon cancer
HDAC4 Upregulation/Downregulation /Mutation Prostate, breast and colon cancer
HDAC5 Under expression Colon cancer, AML
HDAC6 Upregulation Breast, AML
HDAC7 Upregulation Colon cancer
HDAC8 Upregulation Colon cancer
SIRT1 Upregulation/Downregulation Colon cancer
SIRT2 Downregulation, Deletion Glioma
SIRT3 Upregulation Breast cancer
SIRT4 Downregulation AML
SIRT7 Upregulation Breast, thyroid carcinoma
Histone acetyl transferases
P300 Mutation, Translocation, Deletions Colorectal, breast, ovarian,
hepatocellular and oral carcinomas,
CBP Mutation, Translocation, Deletions Colon, breast, ovarian and AML
PCAF Mutation Colon
MOZ Translocation Hematologic malignancy
MORF Translocation Hematologic, uterine leiomyomata
Tip60 Downregulation, translocation Colorectal, prostate cancer
GCN5 Downregulation, mutation Prostate, breast ovary
PCAF Rare mutation Colon cancer
HBO1 Upregulation Testis, breast, ovary and bladder cancer
Histone methyltransferase
MLL1 Translocation, Amplification Hematologic malignancies
MLL2 Amplification Glioma, pancreatic cancer
MLL3 Mutation, Deletion Hematologic malignancies, colon cancer
MLL4 Amplification Solid tumor
SUV39H1-2 Mutation overexpression Ovarian, colon
G9a Gene Repression Colon, gastric, breast cancer
RIZ1/ PRDM2 Underexpression, Mutations Colorectal, gastric cancer
EVI1 Chromosomal rearrangement Myeloid leukemia
EZH2 Amplification, Upregulation Prostate, breast ovarian cancer
SUZ12 Upregulation Prostate, breast ovarian cancer
BMI1 Upregulation Prostate, breast ovarian cancer
NSD1 Translocation, Upregulation AML
NSD2 Translocation Multiple myeloma
NSD2 Translocation Multiple myeloma
NSD3 Translocation, Amplification AML, breast cancer
SYMD2 Upregulation Breast, colon cancer
DOT1 Upregulation AML
Histone demethylases
LSD1/BHC110 Downregulation Breast cancer
JARID1A-D Upregulation /Inactivation mutation Leukemia, prostate, breast renal carcinoma
JHDM2a, 2b Upregulation T-cell lymphoma
JMJD2A/JHDM3A Upregulation Squamous cell carcinomas, lung cancer
JMJD3 Downregulation Lung, liver cancer
UTX Inactivation mutation Squamous cell carcinomas, renal cell carcinomas

CBP, CREB binding protein; Dot1, disruptor of telomeric silencing EZH2, enhancer of zest homolog2; Gcn5, general control
nonderepressible; HBO1, histone acetyltransferase binding to ORC1; HDAC, histone deacetylase; JARID, Jumonji, AT-rich
interactive-domain JHDM, JmjC domain-containing histone demethylase 1; JMJD, Jumonji domain containing 2; LSD1, lysine
specific demethylase 1; MLL, myeloid/lymphoid or mixedlineage leukemia-associated protein; Morf, MOZ-related factors; MOZ,
monocytic leukemia zinc finger protein; NSD1, nuclear receptor-binding SET-domain protein 1; p300, E1A binding protein p300;
PCAF, p300/CBP-associated factor; PRMT, protein arginine methyltransferase 1; RIZ1, retinoblastoma protein-interacting zinc
finger 1; SIRT, Sir2 histone deacetylase gene family; SMYD2, split SET/MYND domain-containing histone H3 lysine 36-specific
methyltransferase; SUV39H, suppressor of variation 3-9 homolog; TIP60, human HIV-1 Tat interactive protein 60; UTX, ubiquitously
transcribed tetratricopeptide repeat, X chromosome.

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Epigenetics and cancer

Table 3. MicroRNAs alteration in various human cancers

MicroRNAs Target gene(s) Alterations Cancer type

miR-127 Bcl-6 Upregulation Bladder cancer

miR-124 CDK6 Upregulation Colon cancer
miR-223 NFI-A, MEF2C Upregulation Acute myeloid leukemia
miR-34b/34c p53 network, CDK6, E2F3 Upregulation Colon cancer
miR-17, miR-92 c-MYC Upregulation Lung cancer
miR-372, miR-373 RAS, p53,CD44 Upregulation Testicular germ cell tumor and breast
cancer
miR-21 PDCD4, PTEN, TPM1, REC, Upregulation Glioblastoma, breast, lung, prostate,
TIMP3, BCL2 colon and cervical cancer
miR-155 RHOA Upregulation Burkitt’s lymphoma, breast, colon, and
lung cancers
miR-146 NF-κB Upregulation Breast, pancreas and prostate cancers
miR-92b PRMT5 Upregulation Brain primary tumors
miR-520 CD44 Upregulation Breast cancer
miR-10b HOXD10 Upregulation Metastatic breast cancer
miR-9 CDH1 Upregulation Breast cancer
miR-127, miR-199a BCL6, E2F1 Upregulation Cervical cancer
miR-421 CBX7, RBMXL1 Upregulation Gastric cancer
miR-1228, miR-195, CDKN2A, NF2, and JUN Upregulation Malignant mesothelioma
miR30b, miR-32, miR345
miR-190, miR-196 HGF Upregulation Pancreatic cancer
miR-125 AKT, ERBB2-4, FGF, FGFR, IGF, Upregulation Breast cancer
MAPKs, MMP11, SP1, TNF,
VEGF
miR-29 DNMT3a&b Upregulation Lung cancer
miR-1 FoxP1 Upregulation Hepatocarcinoma
miR-9-3 E-cadherin Upregulation Colorectal, melanoma, head and neck
cancer
miR-34a CD44, Notch1 Upregulation Hematological, prostate, breast cancer
miR-181c Notch4, K-Ras Upregulation Gastric, colorectal cancer
miR-200c, miR-141, ZEB1/ZEB2 Upregulation Colorectal, breast, lung cancer
miR-429
miR-126 CRK1, PIK3R2, SPRED1, Downregulation Breast and lung cancer
VCAM1
miR-146a, miR-146b ROCK1, IRAK1, TRAF6 Downregulation Prostate cancer and papillary thyroid
carcinomas
miR-340, miR-421, miR-658 MYC, RB, PTEN Downregulation Lymph node metastasis and gastric
cancer
let-7a-3 RAS, IGF-II Downregulation Lung and ovarian cancer
miR-221, miR-222 CDKN1C/P57 and CDKN1B/P27 Downregulation Hepatocellular carcinoma
miR-9 NF-κB Downregulation Ovarian and lung cancer
miR-218, miR-145 PXN Downregulation Breast, lung and prostate cancer
miR-25, miR-32, miR-142 ITGAα1 Downregulation Lung cancer and solid tumor
miR-124, miR-183 ITGBβ1 Downregulation Lung cancer
miR-143 ERK5 Downregulation Cervical cancer
miR-372, miR-373 LATS2 Downregulation Testicular germ cell cancer
miR-181 VGFR Downregulation Lung cancer
miR-370 MAP3K8 Downregulation Cholangiocarcinoma
miR-342 ER, PR and HER2 Downregulation Breast and colon cancer
miR-145 ER Downregulation Colon and breast cancer
miR-124, miR-183 ITGB1 β Downregulation Lung cancer
miR-101 EZH2 Downregulation Prostate, breast , Lung
miR-143 DNMT3a Downregulation Colorectal cancer
miR-9-1 FGF family Downregulation Breast, ovarian, pancreas cancer
miR-137 CDK6, E2F6, LSD Downregulation Glioblastoma, oral, colorectal cancer
miR-129-2 SOX4 Downregulation Gastric, endometrial, colorectal cancer
miR-145 OCT/SOX2/KLF Downregulation Prostate cancer
miR-148 TGIF2 Downregulation Colorectal, melanoma, head and neck
cancer

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Kanwal and Gupta
Table 3. Continued

MicroRNAs Target gene(s) Alterations Cancer type

miR-199a IKKB Downregulation Hepatocarcinoma, testicular ovarian

cancer
miR-203 ABL1 Downregulation Hematological, liver cancer
miR-205 ZEB1/ZEB2 Downregulation Bladder, breast, prostate cancer
miR-335 SOX4/TNC Downregulation Breast cancer
miR-342 PDGFRA Downregulation Ovarian, breast cancer

BCL2, B-cell lymphoma 2 protein; CBX7, chromobox 7; CD44, cluster differentiation 44; CDH1, cadherin-1; CDK6, cyclin D kinase
6; CDNK2A, cyclin-dependent kinase inhibitor 2A; CRK1, Cdc2-related kinase1; ER, estrogen receptor; ERBB2-4 or (HER4), human
epidermal growth factor receptor 4; ERK5, extracellular signal-regulated kinase 5; FGFR, fibroblast growth factor receptor; FOXP1,
forkhead box protein O1; HGF, hepatocyte growth factor; HOXD10, homeobox D10; IGF-II, insulin-like growth factor 2; IRAK1,
interleukin-1 receptor associated kinase-1; KLF, Kruppel-like factors; LATS2, large tumor-suppressor, homolog 2; MAPKs, mitogen-
activated protein kinase; MEF2C, myocyte enhancer factor 2C; MMP11, matrix metalloproteinase11; NF2, neurofibromatosis, type
2; NFIA, nuclear factor 1 A-type; NF-kB, nuclear factor-κB; OCT4, octamer-binding transcription factor 4; P53, tumor protein
53; PDcD4, programmed cell death 4; PDGFRA, alpha-type platelet-derived growth factor receptor; PIK3R2, Phosphatidylinositol
3-kinase regulatory subunit beta; PR, progesterone receptor; PRNT5, protein arginine N-methyltransferase 5; PTEN, phosphatase
and tensin homolog; PXN, paxilin; ITGβ1, integrin beta-1; RAS, rat sarcoma; Rb, retinoblastoma; RBMX L1, RNA binding motif protein
X-linked; RECK, reversion inducing cysteine rich protein kazal Motif; ROCK1, rho-associated, coiled-coil containing protein kinase 1;
ROHA, Ras homolog gene family member A; SOX4, SRY (sex determining region Y)-box 4; SPRED1, sprouty-related, EVH1 domain
containing 1; TNFα, tumor necrosis factor-alpha; TPM1, tropomyosin 1; TRAF6, TNF receptor associated factor 6; VCAM, vascular
cell adhesion molecule; VEGF, vascular endothelial growth factor; ZEB1, zinc finger E-box-binding homeobox 1.

gene body (26). Loss of acetylation is mediated by silencing of OCT, SOX2 and KLF4 in human embryonic
HDACs that have been found to be over-expressed stem cells; these genes are required for cell self-renewal
or mutated in different tumor types. Aberrant expres- and pluripotency maintenance (43). Interestingly, it is
sion of both HMTs and HDMs are observed in var- becoming apparent that the expression of epigenetic
ious cancer types (36). A recent study has described regulatory enzymes such as DNMT, HATs, and HMTs
inactivating mutations in the histone methyltransferase can be controlled by miRNAs (44). In particular, the
SETD2 and in the histone demethylase UTX and miRNA-29 family can directly regulate the expression
JARID1C in renal carcinomas (36, 37). H3 acetyla- of DNMTs such that downregulation of this family of
tion and H3K9 dimethylation can discriminate between miRNAs in small-cell lung cancer results in increased
cancerous and nonmalignant prostate tissue and H3K4 expression of DNMT3A and 3B causing a global
trimethylation can predict occurrence of prostate- genomic hypermethylation and specific methylation-
specific antigen serum level elevation after prosta- induced silencing of tumor-suppressor genes such as
tectomy for cancer (28). EZH2 (enhancer of zeste FHIT and WWOX (45, 46).
homolog 2) expression is an independent prognostic
marker that is correlated with the aggressiveness of
prostate, breast and endometrial cancers (38). Influence of epigenetics on cancer genetics
Because abnormal cell proliferation is a hallmark It is evident that discrete genetic alterations in neo-
of human cancers, it seems possible that miRNA plastic cells alone cannot explain multistep carcinogen-
expression patterns might denote the malignant state. esis whereby tumor cells are able to express diverse
Indeed, altered expression of a few miRNAs has phenotypes during the complex phases of tumor devel-
been found in some tumor types (39, 40). The first opment and progression. In fact, cancer cells have
association between miRNA and cancer development an altered epigenome compared to the tissues from
was described in chronic lymphocytic leukemia with which they arise. Deregulated epigenetic mechanisms
chromosome 13q14 deletion. This deletion deregulates may initiate genetic instability, resulting in the acqui-
miRNA-15 and miRNA-16 (41). Most of the targets sition of genetic mutations in tumor-suppressor genes
of these two miRNAs are involved in cell growth and activating genetic mutations in oncogenes. More-
and cell cycle. The let-7 is one of the most widely over, epigenetic disruptions in tumors are generally of a
studied miRNA families in cancer. Alterations of let-7 clonal nature, indicating occurrence in early generations
function have been described in several human cancer of cells (47). It is well known that 5-methylcytosine
types, including carcinomas of the head and neck (m5C) residues are ‘hot spots’ for mutations, which
region, lung, colon, rectum and ovary. It acts mainly can destabilize gene structure and function. One-third
as a tumor-suppressor miRNA (28). miRNA-145 is a of germ-line point mutations leading to human genetic
well-known tumor-suppressor miRNA downregulated diseases occur at CpGs and most of these mutations are
in many human cancers owing to aberrant DNA C→T transitions (48). This is because m5C is highly
methylation of its promoter and/or p53 mutations (42). mutable by deamination, resulting in transitional muta-
This miRNA is a pluripotency repressor which regulates tions (i.e. C→T) at CpGs. In view of the symmetry of

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Epigenetics and cancer
these CpG motifs, the methylcytosine on the opposite pattern, but environmental factors also play an impor-
strand may also be affected, leading to (G→A) changes. tant role. Polymorphisms in MTHFR, DNMT3b, and
As a consequence, CpGs are hot spots for mutations, MTR genes, involved in methyl metabolism or DNA
in a variety of genes. (48, 49) G→A transitions are methylation, are some of the obvious genetic candidates
found in 44.8% cases of leukemia and myelodysplasia, for variation in methylation in both normal and tumor
and in 60% of colon cancer cases. C→T and tandem tissues (64).
CC-TT mutations are found in basal cell and squamous
cell carcinomas (50). Methylation increases the rate of
hydrolytic deamination and also increases the reactivity Epigenetic biomarkers
of neighboring guanines to electrophiles (50, 51). The Methylated DNA sequences represent potential bio-
oxidation of m5C may contribute to the high frequency markers for diagnosis, staging, prediction of progno-
of C→T transitions at CpG sequences. Oxygen radicals sis and monitoring of response to therapy. Epigenetic
can react with m5C to oxidize the 5, 6-double bond; the markers can be evaluated in resected tumors or in body
intermediate product, m5C glycol, then deaminates to fluids (65). For example, the frequency of occurrence
form thymine glycol (52, 53). Oxidative stress can con- of hypermethylated CDH13, MYOD1, MGMT, p16 INK4a
tribute to tumor development not only through genetic
and RASSF1A genes varies significantly among can-
but also through epigenetic mechanisms. As noted ear-
cer types. These changes can be detected in plasma
lier, the presence of hydroxyl radicals can cause a wide
DNA and urine. Recently, combined hypermethylation
range of DNA lesions including base modifications,
assays for small number of genes such as RASSF1A,
deletions, strand breakage and chromosomal rearrange-
RARβ2, APC and GSTP1 have been used to discrim-
ments. Such DNA lesions have been shown to interfere
inate between benign and cancerous changes in the
with the ability of DNA to function as a substrate for the
prostate (66, 67). Furthermore, repetitive DNA ele-
DNMTs, resulting in global hypomethylation (54). The
ments such as SINEs and LINEs and other repetitive
presence of 8-OHdG in CpG dinucleotide sequences has
sequences are often hypomethylated. Their presence has
been shown to strongly inhibit methylation of adjacent
been used to characterize some human cancers, but their
cytosine residues (55, 56). In addition, 8-OHdG may
clinical utility remains questionable (68).
not be recognized by proof-reading enzymes and thus
may persist as a mutation resulting in G→T transver- Histone modification patterns also provide prognos-
sions (57, 58). These studies suggest that oxidative tic and diagnostic information in cancer. Repressive
DNA damage can affect patterns of DNA methylation chromatin structures characterized by particular his-
leading to aberrant gene expression and possibly con- tone modifications such as H3K9, H3K27 and H4K20
tributing to the development of malignancy. methylation may precipitate DNA methylation. Gener-
alized changes in chromatin structure and histone mod-
ification, such as increased H3K4 dimethylation and
Hereditary cancer genes and cancer predisposition H3K18 acetylation activation, are associated with poor
prognosis (69). Whether the extent of these changes
Studies of familial cancer have identified a group of
correlates with alteration in gene activity is a major
genes whose mutational inactivation results in pre-
limitation.
disposition to a characteristic spectrum of cancers.
More recently, miRNA has been proposed as poten-
The tumor-suppressor gene, RB which is mutated in
tial epigenetic biomarkers in the diagnosis of cancer.
retinoblastoma, was the first hereditary cancer gene
Some of the miRNA such as miR-199a, miR-200a,
to be identified. Subsequently, other tumor-suppressor
miR-146, miR-214, miR-221 and miR-222 have been
genes operating through a diverse range of mechanisms
found to be upregulated, whereas miR-100 is down-
were identified in other familial cancers, e.g. adeno-
regulated in human cancers (44). The miRNA let-71
matosis polyposis coli (APC) mutations were identi-
has been recently designated as a tumor-suppressor and
fied in cases of familial adenomatous polyposis coli
miR-429, miR-200a and miR-200b were found to be
and p16 INK4a mutations were identified in cases of
familial melanoma (59). DNA repair genes such as the clustered on a single primary transcript regulated by the
BRCA1, MLH1, and MSH2 are also often involved epithelial-to-mesenchymal transition (70). Studies have
in predisposition to familial cancer (60, 61). Spe- shown that two other miRNAs, miR-21 and miR-181a
cific allele sequence variants such as single nucleotide can be used to identify the presence or absence of a
polymorphisms (SNPs) affect the probability of CpG malignant phenotype. A group of 27 miRNA has been
islands methylation in the cis region. Cis-acting DNA shown to be significantly associated with chemother-
mutations have been shown to cause constitutional apy response and proposed as possible prognostic and
epi-mutations early in cancer development (62). One diagnostic biomarker (71, 72).
example of epigenetic silencing caused by sequence
alterations in cis is the methylation of expanded CGG Conclusions
repeats within the FMR1 promoter in the fragile X
mental retardation syndrome (63). Little is known about The epigenetic modification patterns associated with the
what causes variation in methylation levels and how this development and progression of cancer are potentially
variation relates to future pathogenesis. Genetic factors clinically useful. The development of DNA methylation
may play key roles in maintaining a normal methylation markers may prove useful for early cancer detection,

309
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Kanwal and Gupta
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