DNA Methylation and Cancer Development: Molecular ... - Springer Link

Cell Biochem Biophys (2013) 67:501–513 DOI 10.1007/s12013-013-9555-2

REVIEW PAPER

DNA Methylation and Cancer Development: Molecular Mechanism Haleh Akhavan-Niaki • Ali Akbar Samadani

Published online: 19 March 2013 Ó Springer Science+Business Media New York 2013

Abstract DNA methylation is a significant regulator of gene expression, and its role in carcinogenesis recently has been a subject of remarkable interest. The aim of this review is to analyze the mechanism and cell regulatory effects of both hypo- and hyper-DNA methylation on cancer. In this review, we report new developments and their implications regarding the effects of DNA methylation on cancer development. Indeed, alteration of the pattern of DNA methylation has been a constant finding in cancer cells of the same type and differences in the pattern of DNA methylation not only occur in a variety of tumor types, but also in developmental processes Furthermore, the pattern of histone modification appears to be a predicator of the risk of recurrence of human cancers. It is well known that hypermethylation represses transcription of the promoter sections of tumor-suppressor genes leading to gene silencing. However, hypomethylation also has been identified as a cause of oncogenesis. Furthermore, experiments concerning the mechanism of methylation and its control have led to the discovery of many regulatory enzymes and proteins. This review reports on methods developed for the detection of 5-hydroxymethylcytosine methylation at the 5-methylcytosine of protein domains in the CpG context compared to non-methylated DNA, histone modification, and microRNA change. Keywords DNA methylation Cancer Oncogenesis Histone modification Epigenetics MicroRNA

H. Akhavan-Niaki A. A. Samadani (&) Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran e-mail: [email protected]

Introduction DNA methylation is an important biochemical process involved in normal development of higher organisms. It comprises the addition of a methyl group to the carbon 5 of the pyrimidine ring of cytosine or the nitrogen 6 of the purine ring of adenine. This modification can be inherited through cell division. As a vital part of normal organismal development and cellular differentiation in higher organisms, DNA methylation constantly changes the gene expression pattern in cells; for instance, cells programmed to be pancreatic islets during embryonic development remain pancreatic islets throughout the life of the organism without the necessity of continuous extracellular signaling. DNA methylation is typically removed during zygote formation and re-established through successive cell divisions during development [1]. Recent researches show that hydroxylation of methyl groups occurs rather than complete removal of methyl groups in zygote. However, some methylation modifications that regulate gene expression are inheritable and are referred to as epigenetic regulation [1]. Beside its involvement in normal development, due to its implication in many other regulatory processes, DNA methylation is the subject of particular interest. For instance, it may suppress the expression of viral genes and other deleterious elements that have been incorporated into the genome of the host over time. DNA methylation also forms the basis of chromatin structure, which enables cells to form the myriad characteristics necessary for multicellular life from a single immutable sequence of DNA. DNA methylation also plays a crucial role in the development of nearly all types of cancer [2, 3]. It has been speculated that DNA methylation might play a role in the onset or course of cancer. In the past decade, a

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solid foundation for this view has been arranged by a series of reports documenting various changes in the DNA methylation patterns or in DNA methyltransferase expression levels in transformed cells in vitro and in vivo [4–8]. Adding to this mostly correlative body of evidence, some exciting new insights have come from some recent reports that provide a direct and possibly causal connection between DNA methylation and cancer [9–12]. Even though most cytosine methylations take place on 50 CG30 sequences also called CpG, some include CpA and CpT dinucleotides [13]. As DNA is made up of four bases, thus, there are 16 possible dinucleotide combinations. Therefore, the CpG dinucleotide is expected to occur at a frequency of nearly 6 % [13]. However, the actual prevalence is only 5 to 10 % of its anticipated frequency. This CpG suppression may be related to the hypermutability of methylated cytosine [14]. The human genome is not methylated uniformly and includes sections of methylated segments interspersed within unmethylated parts. Moreover, small regions of genome, called CpG islands, ranging from 0.5 to 5 kb and occurring on average every 100 kb, have distinctive properties [15]. These regions are unmethylated, GC rich (60 to 70 %), with a ratio of CpG to GpC of at least 0.6, and thus do not present the characteristic imbalance reported for CpG dinucleotides. Approximately half of all the genes in humans have CpG islands, and this is valid both for housekeeping and tissue-specific genes [16]. DNA methylation is brought about by a group of enzymes known as the DNA methyltransferases (DNMT). The DNMTs known to date are DNMT1, DNMT1b, DNMT1o, DNMT1p, DNMT2, DNMT3A, DNMT3b with its isoforms, and DNMT3L. Methylation can be de novo (when CpG dinucleotides on both DNA strands are unmethylated) or maintenance (when CpG dinucleotides on one strand are methylated). DNMT1 has de novo as well as maintenance methyltransferase activity, while DNMT3A and DNMT3b are powerful de novo methyltransferases. The importance of these enzymes has been shown using several experiments on mouse in which the gene deficient fetus dies early in development or immediately after birth [17]. In addition to the DNMTs, other members of methylation machinery include demethylases, methylation centers triggering DNA methylation, and methylation protection centers [8]. DNA methylation patterns are established early in embryogenesis and are very finely controlled during development. The enzymes that actively demethylate DNA include 5-methylcytosine glycosylase, which removes the methylated cytosine from DNA, leaving the deoxyribose intact (eventually, local DNA repair adds back the cytosine in nucleotide form), and MBD2b, which refers to an isoform that results from initiation of translation at the second

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Cell Biochem Biophys (2013) 67:501–513

methionine codon of the gene encoding methyl-CpG binding domain 2 (MBD2) protein [12]. MBD2b lacks glycosylase or nuclease activity and is thought to cause demethylation by hydrolyzing 5-methylcytosine to cytosine and methanol. However, these mechanisms were not found in all studied systems [18, 19].

DNA Methylation Changes in Tumors Hypomethylation is observed in a wide variety of malignancies (Table 1). The pericentric heterochromatin regions on chromosomes 1 and 16 are heavily hypomethylated in patients with immunodeficiency, centromeric instability, facial abnormalities, and in many cancers. A mutation of DNMT3b has been found in those patients leading to instability of the chromatin. Hypomethylation has been hypothesized to contribute to oncogenesis by activation of oncogenes such as cMYC and H-RAS or by activation of latent retrotransposons [18–22]. Long interspersed nuclear elements are the most plentiful mobile DNAs or retrotransposons in the human genome. Hypomethylation of these mobile DNAs causes transcriptional activation and has been found in many types of cancer, such as urinary bladder cancer. Hypomethylation of the mobile DNA can also cause disruption of expression of the adjacent genes. The L1 mutational insertions have been found to disrupt the APC and CMYC genes in colon and breast cancers, respectively [22–24]. Housekeeping genes have a non-methylated CpG island tightly associated with their promoter. Such genes tend to be expressed ubiquitously and are regulated by DNA methylation [34]. In a recent survey by Yeivin and Razin, a large majority of tissue-specific genes showed a correlation between gene activity and hypomethylation of the promoter region [35]. A weaker correlation with CpG islands has been observed in many cells growing in tissue culture. These CpG islands are not methylated in normal tissues in vivo and have been

Table 1 Some malignancies that can be caused by hypomethylation Specific Hypomethylation

Solid tumors Metastatic Hepatocellular cancer Cervical cancer Prostate tumors Hematologic malignancies B cell chronic lymphocytic leukemia

Global Hypomethylation

Breast cancer Cervical cancer Brain cancer


found to be associated with genes that are not essential for growth in culture, suggesting that gene silencing by methylation can be of selective advantage for cell growth [36, 37]. There have also been many reports on regional increases in DNA methylation levels (Fig. 1). There are regional hotspots for hypermethylation on chromosomes 3p, 11p, and 17p in a variety of human tumors [25]. These include CpG islands areas that are normally never methylated in vivo. This is reminiscent of the changes that occur at CpG islands at non-essential genes in tissue culture [26, 27]. Evidences indicate that Rb tumor-suppressor gene may become inactive through hypermethylation in sporadic retinoblastoma. Transient transfection experiments showed that specific hypermethylation in the promoter region of Rb could reduce its expression to 8 % of an unmethylated control. It is possible, therefore, that hypermethylation of tumor-suppressor genes leading to gene inactivation results in a selective growth advantage of the transformed cells [28–30]. There are examples of parental-origin-specific allelic loss of tumor-suppressor genes which suggest a role for genomic imprinting. Although a role for DNA methylation in genomic imprinting seems well established, little is known about the precise mechanism in these cases [30–33].

Implication of Folic Acid in DNA Methylation and Cancer Promotion The role of nutrients in affecting gene expression through interaction with genetic polymorphism and modulation of DNA methylation has received considerable attention recently. The disruption of homeostasis in the vitamindependent one-carbon (methyl group) metabolism affects the risk of heart disease, neural tube defects, and cancer. Such disruption can occur as the result of deficiencies of the two essential micronutrients involved in this metabolism: folate and cobalamin [39–42].

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One-carbon metabolism is divided into two main branches: one consists of reactions involving purine and thymidine synthesis, and the other involves synthesis of methionine and S-adenosyl methionine for protein and polyamine synthesis and methylation reactions. An enzyme that shunts methyl groups from the first of these branches to the second is methylenetetrahydrofolate reductase (MTHFR). MTHFR irreversibly converts 5,10-methylenetetrahydrofolate (5,10– CH2–THF) to 5-methyl-THF, which then donates a methyl group to homocysteine to produce methionine [42–49] . When folate intake is sufficient, individuals carrying the variant MTHFR genotypes may have a decreased risk of cancer, because under these conditions, enhanced genomic integrity would be achieved due to an increased availability of methyl groups for conversion of uracil to thymidine as a result of the greater availability of the MTHFR substrate 5,10–CH2–THF for DNA synthesis [50]. Inadequately, low thymidine pools, on the other hand, lead to increased incorporation of uracil into DNA, thereby resulting in strand breaks that are precursors for chromosome translocations and deletions (Fig. 2). When folate intake is low, both DNA methylation and DNA synthesis/repair might be impaired in individuals with some MTHFR variant genotypes, which in turn would result in increased risk of carcinogenesis [51]. Folate deficiency has been shown to result in both hypoand hypergene-specific methylation [52]. In animal studies, folate deficiency has been shown to result in exon-specific hypomethylation of the p53 gene as well as increased DNA methyltransferase activity [53]. However, with continued folate deficiency, an increase in both p53 and genome-wide methylation was observed (Fig. 3) [54].

DNA Methylation as a Marker in Cancer A vast amount of knowledge has been gained in the last few years about altered methylation patterns in human cancers. Tumor-specific methylation changes in different

Fig. 1 Hypermethylation and Hypomethylations ways in cancer. TSG Tumor-suppressor gene

: Hypomethylation

Hypermethylation

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Fig. 2 Models for the role of 5-methylcytosine in cancer Fig. 3 Folate and regulation of DNA synthesis, repair, and methylation. Folate deficiency may decrease thymidylate synthesis, inhibit DNA repair, induce imbalance of DNA methylation, histone modification, and finally cause carcinogenesis

genes have been identified and documented. The potential clinical application of this information is in cancer diagnosis, prognosis, and therapeutics [55, 56]. Recent advances in techniques for detection of methylation include powerful tools such as sodium bisulfite conversion, DNA microarray, restriction landmark genomic

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scanning, and CpG island microarrays. The sodium bisulfite method is ideal for mapping the normal and aberrant patterns of methylation. Bisulfite converts unmethylated cytosines to uracil, leaving methylated cytosines unchanged. After bisulfite modification, there are a number of methods available to study CpG island methylation. These


include sequencing, methylation-specific polymerase chain reaction, combined bisulfite restriction analyses, methylation-sensitive single nucleotide primer extension, and methylation-sensitive single-strand conformational polymorphism. Software programs are available to help design primers for bisulfite-treated DNA. To be useful as a routine diagnostic tool, the actual methylation detection method has to be sensitive, quick, easy, and reproducible. Of the various techniques available, methylation-specific polymerase chain reaction seems to be most useful at present [57–59]. An early diagnosis is critical for the successful treatment for many types of cancer. Some traditional methods of diagnosis including cytology, histopathology, immunohistochemistry, serology are useful, but molecular markers can more accurately subclassify the tumors. The methylation profile can distinguish tumor types and subtypes and perhaps predict the response to chemotherapeutic agents and survival. Methylation modifications often precede apparent malignant changes and thus may be of use in early diagnosis of cancer. Moreover, sensitive detection of cancer cells could be obtained from plasma in many cases. Examples include bladder cancer, breast cancer, colorectal cancer (CRC), esophageal cancer, gastric cancer, lung cancer, prostate cancer, head and neck tumors, and liver cancer [60] (Tables 2, 3, 4). In addition, samples obtained by exfoliative cytology, endoscopic brush techniques, and biopsy, as well as urine, saliva, and sputum, can be used. These are non- or minimally invasive procedures and often much easier to collect and process. The sensitivity and specificity of DNA methylation markers in cancer diagnosis depends on several factors, including the type of cancer and the gene to be studied, the type of body fluid to be used, and the technique involved. The assay needs to be standardized and shown to be useful in a prospective fashion before it can become clinically useful [60, 61].

DNA Methylation Role in Mutation Occurrence The high rate of mutagenesis of 5-methylcytosine compared to other nucleotides has been widely documented in the literature. The estimated mutation rate of CpG dinucleotides is 10- to 40-fold that of other dinucleotides. CpG dinucleotides occur at a frequency of only about 1 % of all dinucleotides in the human genome. Nevertheless, transitions at CpG dinucleotides accounted for 25 % of 254 independent point mutation found in the p53 gene in human tumors in one survey and for 33 % of 324 p53 mutations in another survey [63]. In yet another compilation of tumors with p53 mutations, 7 % of 263 cases of human lung cancer, 10 % of 119 cases of liver cancer in

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low-incidence areas, and 41 % of 180 cases of colon cancer were found to have transitions at CpG dinucleotides [64]. These differences are believed to reflect the balance issues between mutagenic events due to endogenous CpG transitions and those due to exogenous carcinogenic agents such as those present in tobacco smoke. Rideout et al. showed that cytosine residues in the p53 gene known to have undergone somatic mutation were methylated in all normal human tissues analyzed [65]. The endogenous mutagenic activity of 5-methylcytosine is operative in the germ line as well. In a survey of 139 point mutations causing human genetic disease, 52 were in CpG dinucleotides (37 %) [66]. In an analysis of 216 mutations in the coagulation factor IX gene, giving rise to hemophilia B, 97 mutations were CpG transitions (45 %) [67]. This high contribution of CpG mutations is also true for germline mutations in tumor-suppressor genes. Two out of six germline mutations in the p53 gene in cases of Li–Fraumeni syndrome were CpG transitions. Three out of eight germline mutations in patients with retinoblastoma and four out of eight germline mutations in the APC gene in patients with familial Adenomatous Polyposis Coli were found to be CpG transitions [67–70].

DNA Hypomethylation and Current Method of Analysis A decrease in the amount of cellular cytosine methylation is observed in many neoplastic tissues and is related to poor prognosis or clinical severity in several cancer types, including prostate, ovarian, and chronic myelogenous leukemia (reviewed in [71]). DNA hypomethylation varies not only between cancer types but also in the timing of demethylation according to disease stage and grade and causes chromosomal instability, aberrant gene expression, loss of imprinting and retro transposon activation. Hypomethylation occurs both in global (genome-wide) and in gene-specific contexts. In certain cancers, specific hypomethylated genes have been identified (P-cadherin and synuclein in breast cancer [72, 73]. p53 in lung cancer [74], while global (genome wide) hypomethylation is observed in virtually all tumors making hypomethylation an equally attractive biomarker candidate [71]. Present methods for the analysis of hypomethylation include high-performance capillary electrophoresis or which measure 5 mC as a percentage of total cytosine, decreases in signal with 5 mC antibody-based methods (immunohistochemistry, blots) or PCR based bisulfite-based methods [75], geared to examine the methylation status of satellite repeat sequences and transposable elements such as Alu elements and long interspersed nucleotide elements [76–78] (Table 5).

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Table 2 Associations between serum and/or plasma DNA methylation and cancer risk Genes

Source

Sample size (cases/controls)

Assay

References

Breast cane RASSF1A

Plasma

33/29

MSP

[53]

PC

Serum

79/19

QMSP

[52]

Plasma/serum

36/30

EpiTyper assay

[65]

Serum

86/49

MSP

[116]

RASSF1A

Serum

47/30

MSP

[54]

APC

Serum

60/22

Methylight

[117]

Plasma

20/24

Methylight

[118]

Serum

100/100

MSP

[119]

41/43

QMSP

[120]

ESR1 RASSF1A APC BIN1 BMP6 BRCA1 CST6 ESR-b GSTP1 P16 P21 TIMEP3 Bladder cancer P16INK4a Gastric cancer

Hmlh1 TIMP3 Head and neck squamous cell carcinoma p15 p16 Lung cancer DAPK MGMT P16INK4a RASSF1A RAP-b Nasopharyngeal carciboma CDH1

Plasma

DAPK p15 p16 RASSF1A Prostate cancer Gstp1

Serum

168/11

QMSP

[55]

Ptgs2

Serum

46/49

MSP

[121]

Tig1 14-3-3d AR GSTPI MSP methylation-specific PCR, QMSP quantitative methylation-specific PCR, MSRE methylation-sensitive restriction enzyme, HPCE highperformance capillary electrophoresis, LC/MS liquid chromatography/mass spectrometry, COBRA combined bisulfite restriction analysis

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507

Table 3 Associations between serum and/or plasma DNA methylation and cancer prognosis Genes

Outcome


Assay

References

Breast cancer RASSF1Ab

Relapse-free survival

13/148

Methylight

[122]

APC

Overall survivala

17/85

Methylight

[123]

PITX2

Overall survival

428

Methylight

[57]

RASSF1A

Distant disease-free 12/15

MSP

[124]

RASSF1A

Survival Bladder cancer P14ARF


Cervical cancer MYOD1


53/40

Methylight

[125]

CDH1 CDH13


53/40

Methylight

[126]

Overall survival

28/77

Methylight

[127]

Colorectal cancer HLTF HPP1 Hmlh1 Esophageal cancer DAPK

Overall survival

59

QMSO

[128]

APC

Overall survival

52

QMSP

[129]

Overall survival

32/26

Methylight

[117]

Overall survival

85

COBRA

[130]

Gastric cancer APC CDH1 Hepatocellular carcinoma LINE1 Lung cancer DAPK

Overall survival

76

QMSP

[128]

MGMT 14-3-3d

Overall survival

75/40

MSP

[131]

Overall survival

78/53

MSP

[132]

Distant -free

55/55

REQP

[133]

Ovarian cancer hMLHb Prostate cancer GSTP1

Survival MSP methylation-specific PCR, QMSP quantitative methylation-specific PCR, MSP methylation-specific PCR, COBRA combined bisulfite restriction analysis, REQP restriction endonuclease quantitative PCR a Hypermethylation of genes worsened prognosis b

Measurements were done at disease endpoint

MicroRNA in Carcinogenesis MicroRNA (miRNA) is a non-coding RNA which length is about 18–22 nucleotides. miRNAs are principally involved in gene expression regulation [79–81]. They have been found to play an important role in cancer initiation and progression [82]. Furthermore, the patterns of miRNAs expression were considered as diagnostic, prognostic, and chemo sensitivity markers in various types of cancer. Loss of miR-133a and gain of miR-224 are associated with colorectal tumorigenesis. Reduced expression of

miR-143 and miR-145 were found in CRC and adenomatous polyps [83]. Chemically modified miR-143 (miR143BP) has improved nuclease-resistance and may serve as RNA medicine for the treatment for CRC [84]. The level of miR-92 and miR-17-3p has been reported to be significantly higher in the plasma of colon cancer patients compared with healthy controls and is suggested as potential markers for CRC. Stool miR-17-92 clusters and miR-135 are also involved in significant increase in sensitivity to 5-FU and cell migration and invasion inhibition [84–90]. Plasma miR-141 is reported to be a novel biomarker in

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Table 4 Population validation methylation-based biomarkers using plasma/serum DNA Genes

Source


Assay

Sensitivity (%)

Specificity

References

Plasma

93/76

QMSP

62

87

[134]

Breast cancer APC, GSTP1, RASSF1A, RARb2 Colorectal APC,MGMT, RASSF2A, Wif-1

Plasma

243/276

MSP

87

92

[59]

SEPT9

Plasma

97/172

Real-time qPCR

72

93

[66]

Serum

50/50

MSP

84

94

[135]

Plasma

33/33

MethDet test

85

61

[67]

CCND2, PLAU, SOCS1, THBS, VHL Prostate cancer

Plasma

30/30

MethDet test

76

59

[67]

GSTP1, RASSF1, RARB2

Serum

83/40

MSP

89

–

[58]

Hepatocellular carcinoma P15, P16, RASSF1A Ovarian cancer BRCA1, HIC1, PAX5, PGR, THBS1 Pancreatic cancer

QMSP quantitative methylation-specific PCR, MSP methylation-specific PCR Table 5 The main methodologies used in DNA methylation analysis Sequence-specific methylation Quantitative methylation-specific PCR (QMSP) Methylation-sensitive restriction enzyme analysis Sensitive restriction-multiplex PCR Combined bisulfite restriction analysis (COBRA) Bisulfite sequencing Pyrosequencing Multiplex ligation-dependent probe amplification (MLPA) Mass array analysis Global methylation

cancer and was significantly associated with regional nodal invasion, vascular invasion, and metastasis. Expression of these miRNAs was restored after treatment with 5-aza-2‘deoxycytidine (AZA, a DNA methyltransferase inhibitor) and 4-phenylbutyric acid (PBA, a HDAC inhibitor) in CRC cell lines [97, 98]. Loss of miR-127 expression was found in HCT116 cells, though expression could be restored by AZA and PBA in a dose-dependent manner [99]. miR-124a expression was downregulated by DNA methylation in HCT116 cells compared with DKO cells (double knockout of DNMT1 and DNMT3b in HCT116 cells) [100].

Restriction landmark genomic scanning (RGLS) Arbitrarily primed methylation-sensitive PCR (AP-MSP) Methylated CpG island recovery assay (MIRA)

Histone Modifications

Differential methylation hybridization (DMH) Analysis of intermethylated sites (AIMS) Methylated DNA immunoprecipitation (MeDIP) Whole-genome shotgun bisulfite sequencing (WGSBS)

detecting metastatic colon cancer, with its high level being associated with poor prognosis of CRC [91]. In stage II colon cancer, high level of miR-320 and/or miR-498 is correlated with progression-free survival [92]. miR-21, miR-20a, and miR155 are also highly expressed in CRC. High level of miR-21 is associated with poor benefit from 5-FU adjuvant chemotherapy in CRC [93–95]. miR-21 expression level was considered an independent predictor of colon cancer prognosis [96]. Epigenetic regulation of miRNAs expression, including DNA methylation and histone deacetylation, was found in CRC. Frequent methylation of miR-9-1, miR-129-2, and miR-137 was observed in CRC but not in normal mucosa. Methylation of miR-3-1 was more frequent in advanced

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Histone modifications, such as phosphorylation, acetylation, or methylation, in localized promoter regions are histone codes for chromatin packing and transcription [101]. In general, methylation of H3K4, H3K36, and H3K79 is linked to gene expression activation, whereas H3K9me2, H3K9me3, H3K27me3, and H4K20 are associated with gene repression [101–104]. Histone acetyltransferases (HATs) and deacetylases (HDACs) are responsible for the addition and removal of acetyl groups to/from lysine residues. In cancer cells, disruption of the balance between HATs and HDACs contributes to transcriptional inactivation of tumor-suppressor genes (TSGs). Cyclin-dependent kinase inhibitor p21WAF1 is repressed by promoter hypoacetylation in the absence of CpG island hypermethylation, and expression can be reactivated by inhibition of HDAC activity [105]. Interestingly, some TSGs with CpG island hypermethylation can also be re-expressed through inhibition of SIRY1, a class III HDAC that increases H4K16 and H3K9 acetylation at


promoters, without affecting the hypermethylation status [106]. Similar to histone acetylation, histone methylation is dynamically regulated by both histone methyltransferases (MTs) and histone different degrees, including mono-,di-, and trimethylation. H3K27-specific HMT (enhancer of zeste homolog 2, EZH2), catalytic subunit of polycombrepressive complex 2 (PRC2), is overexpressed in human cancers, including colon cancer [107]. H3K27me3 is also regulated by RAS signaling pathway and further affects cyclin D1 and E-cadherin expression. Over expression of oncogenic RAS influences global and gene-specific histone modification during the epithelial-mesenchymal transition (EMT) in Coc-2 CRC cells [108]. DNA methylation-mediated gene silencing is closely linked to histone deacetylation [109, 110]. Histone methylation at key lysine residues has been shown to work in concert with acetylation and other modification to provide a histone code that may determine heritable transcriptional states [111]. In lower eukaryotes, methylated H3k9 determines DNA methylation and correlates with transcription repression [112, 113]. DNA methylation maintains key repressive elements of the histone code at a hypermethylated gene promoter in RKO colon cancer cells. Hmlh1, a mismatch repair gene, is often silenced by aberrant CpG island hypermethylation in CRCs [114]. Deacetylated histone H3 (deacetylated histone H3K9 and H3K14) plus methyl-H3-K9 surrounds the unmethylated and active hMLH1 promoter which is embedded in methyl-H3-K4 and acetylated H3 (acetylated histone H3K9 and H3K14). Promoter demethylation, gene re-expression, and finally complete histone code reversal were induced only by inhibition of DNMT and not HDAC [115].

Discussion We have endeavored to afforded an overview of various mechanisms through which DNA methylation could affect oncogenesis. The field is currently in a transition from a phase of correlative documentation to one of experimental manipulation where many important questions remain to be solved. For instance, the molecular mechanisms of how methylation patterns are established and altered in early development will be of significance for understanding the relevance and mechanisms of methylation changes seen in tumor cells. Another crucial issue is the clarification of the putative role, in generating mutations of cytosine residues. According to the present findings (absence of methylation in normal samples and low levels of methylation in cancerous samples), methylation plays an important role in epigenetic modifications. It is evident that DNA methylation plays a significant role in the generation of mutations in human tumors. The high incidence of C-to-T transitions

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found in the p53 tumor-suppressor gene is attributed to the spontaneous deamination of 5-methylcytosine residues [3–6]. The multiple observations linking DNA methylation to cancer can be resolved in a model proposing that the high rate of mutation at CpG residues is due in part to methyltransferase-facilitated deamination. Support for a role of DNA methyltransferase as a mutator enzyme is provided by work with a prokaryotic DNA methyltransferase under methyl-donor-limiting conditions. Methyl-donor-limiting conditions might arise in early stages of tumor development, leading to high rates of methyltransferase-mediated CpG mutagenesis, as seen in human tumors [8–12].

References 1. Law, J. A., Jacobsen, S. E (2010). Establishing, maintaining and modifying DNA methylation patterns in plants and animals. 2. Docherty, S. J., Davis, O. S., Haworth, C. M. M., Plomin, R., & Mill, J. (2010). DNA methylation profiling using bisulfite-based epityping of pooled genomic DNA. Methods, 52, 255–258. 3. Singal, R., & Ginder, G. D. (1999). DNA methylation. Blood, 93, 4059–4070. 4. Laird, P. W. (2003). The power and the promise of DNA methylation markers. Nature Reviews Cancer, 3, 253–266. 5. Baylin, S. B. (1997). Tying it all together: Epigenetics, genetics, cell cycle, and cancer. Science, 277, 1948–1949. 6. Costello, J. F., & Plass, C. (2001). Methylation matters. Journal of Medical Genetics, 38, 285–303. 7. Baylin, S. B. (1997). Tying it all together: Epigenetics, genetics, cell cycle, and cancer. Science, 277, 1948–1949. 8. Cooper, D. N. & Krawczak, M. (1990). Human Genetics 83, 181–188. 9. Bestor, T. H (1992). Embo G 11, 2611–2617. 10. Ehrlich, M., Zhang, X, Y. & Inamdar, N. M. (1990) Mutatation Research 238, 277–286. 11. Bedford, M. T.& Van Helden, P. D. (1987) Cancer Research 47, 5274–5276. 12. Bestor, T., Laudano, A., Mattaliano, R. & Ingram, V. (1988) G Molecular Biology 203, 971–983. 13. Fremont, M., Siegmann, M., Gaulis, S., et al. (1997). Demethylation of DNA by purified chick embryo 5-methylcytosineDNA glycosylase requires both protein and RNA. Nucleic Acids Research, 25, 2375–2380. 14. Wade, P. A., Gegonne, A., Jones, P. L., et al. (1999). Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genetics, 23, 62–66. 15. Rhee, I., Bachman, K. E., Park, B. H., et al. (2002). DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature, 416, 552–556. 16. Paroush, Z., Keshet, I., Yisraeli, G. & Cedar, H. (1990). Cell 63, 1229–1237. 17. Monk, M., Adams, R. L. & Rinaldi, A. (1991) Development 112, 189–192. 18. Yen, R. W., Campbell, T. A., Nelkin, B. D., Yu, J., Jel, D. W., Cumaraswamy, A., Lennon, G. G., Trask, B. J., Celano, P. & Baylin, S. B. (1992) Nucleic Acids Research 20, 2287–2291. 19. Vairapandi, M. & Duker, N. J. (1993) Nucleic Acids Research 21, 5323-5327. 20. Singer, S. J. & Riggs, A. D. (1993) In Jost, J. P. and Saluz, H. P. (ed.), DNA Methylation: molecular biology and biological significance. BirkhauserVerlag, Basel (Switzerland). pp. 358–384.

123

510 21. Wu, J. C. & Santi, D. V. (1987) Journal Biological Chemistry 262, 4778–4786. 22. Rideout, W.III., Coetzee, G. A., Olumi, A. F.& Jones, P. A. (1990) Science 249, 1288–1290. 23. Das P. M., Rakesh, S. (2004) DNA Methylation and cancer. 24. Lam, A. K. Y. (2000). Molecular biology of esophageal squamous cell carcinoma. Critical Reviews in Oncology/Hematology, 33, 71–90. 25. Parkin, D. M., Baray, F., Ferlay, J., & Pisanl, P. (2001). Estimating the world cancer burden: Globocan 2000, International Journal of cancer, 94(2), 153–156. 26. Ducasse, M., & Brown, M. A. (2006). Epigenetic aberrations and cancer. Molecular Cancer, 5, 60. 27. Ohki, L., Shimotake, N., Fujita, N., Jea, J., Ikegami, T., & Nakao, M. (2001). Solution structure of the methly - CpG binding domain of human MBD1 in complex with methylated DNA. Cell, 105, 487–497. 28. Ng, H. H., & Bird, A. (1999). DNA methylation and chromatin modification. Current Opinion in Genetics & Development, 9, 158–163. 29. Costello, J. F. (2001). PlassC: Methylation matters. Journal of Medical Genetics, 38, 285–303. 30. Ordway, J. M., & Curran, T. (2002). Methylation matters: Modeling a manageable genome. Cell Growth & Differentiation, 13, 149–162. 31. Flanagan, H. M., Munoz-Alegre, M., Henderson, S. M., Tang, T., Sun, P., Johnson, N., et al. (2009). Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Human Molecular Genetics, 18, 1332–1342. 32. Moore, L. E., Pfeiffer, R. M., Poscablo, C., Real, F. X., Kogevinas, M., Silverman, D., et al. (2008). Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder cancer study: A case-control study. Lancet Oncol, 9, 359–366. 33. Lim, U., Flood, A., Choi, S. W., Alanes, D., Cross, A. J., Schatzkinm, A., et al. (2008). Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women. Gastroenterology, 134, 47–55. 34. Widschwendter, M., Apostolidou, S., Raum, E., Rothenbacher, D., Fiegl, H., Menon, U., et al. (2008). Epigenotyping in peripheral blood cell DNA and breast cancer risk: A proof of principle study. PLoS ONE, 3, e2656. 35. Ally, M. S., Al-Ghnaniem, R., & Pufulete, M. (2009). The relationship between gene-specific DNA methylation in leukocytes and normal colorectal mucosa in subjects with and without colorectal tumors. Cancer Epidemiology, Biomarkers and Prevention, 18, 922–928. 36. Teschendorff, A. E., Menon, U., Gayther, S. A., Ramus, S. J., Gentry –Maharaj, A., Apostolidou, S., et al. (2009). An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS ONE, 4, e8274. 37. Pedersen, K. S., Bamlet, W. R., Oberg, A. L., de Anderade, M., Matsumoto, M. E., Tang, H., et al. (2011). Leukocyte DNA methylation signature differentiates pancreatic cancer patients from healthy controls. PLoS ONE, 6, e18223. 38. Kristensen, L. S., & Hansen, L. L. (2009). PCRP-based methods for detecting single-loci DNA methylation biomarkers in cancer diagnostics, prognostics, and response to treatment. Clinical Chemistry, 55, 1471–1483. 39. Bibikova, M., & Fan, J. B. (2010). Genome-wide DNA methylation profiling. Wiley Interdisciplinary Reviews Systems Biology and Medicine, 2, 210–223. 40. Gupta, R., Nagarajan, A., Wajapeyee, N. (2010) Advances in genome-wide DNA methylation analysis. Biotechniques 49, iii–xi.

123

Cell Biochem Biophys (2013) 67:501–513 41. Bock, C., Tomazou, E. M., Brinkman, A. B., Meller, F., Simmer, F., Gu, H., et al. (2010). Quantitative comparison of genome-wide DNA methylation mapping technologies. Nature of Biotechnology, 28, 1106–1114. 42. Bibikova, M., Le, J., Barnes, B., Saedinia-Melnyk, S., Zhou, L., Shen, R., et al. (2009). Genome-wide DNA methylation profiling using infinium assay. Epigenomics, 1, 177–200. 43. Yuasa, Y. (2010). Epigenetics in molecular epidemiology of cancer a new scope. Advances Genetics, 71, 211–235. 44. Brait, M., Ford, J. G., Papaiahgari, S., Garza, M. A., Lee, J. I., Loyo, M., et al. (2009). Association between lifestyle factors and CpG island methylation in a cancer-free population. Cancer Epidemiology, Biomarkers and Prevention, 18, 2984–2991. 45. Techendorff, A. E., Menon, U., Gentry-Maharaj, A., Ramus, S. J., Weisenberger, D. J., Shen, H., et al. (2010). Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Research, 20, 440–446. 46. Breitling, L. P., Yang, R., Korn, B., Burwinkel, B., & Brenner, H. (2011). Tobacco-smoking-related differential DNA methylation: 27 k discovery and replication. The American Journal of Human Genetics, 88, 450–457. 47. Terry, M. B., Delgado-Cruzata, L., Vin-Raviv, N., Wu, H. C., & Santella, R. M. (2011). DNA methylation in white blood cells: Association with risk factors in epidemiologic studies. Epigenetics, 6, 828–837. 48. Terry, M. B., Ferris, J. S., Pilsner, R., Flom, J. D., Tehranifar, P., Santella, R. M., et al. (2008). Genomic New York City birth cohort. Cancer Epidemiology, Biomarkers and Prevention, 17, 2306–2310. 49. Zhang, F. F., Morabia, A., Carroll, J., Gonzalez, K., Fulda, K., Kaur, M., et al. (2011). Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population. The Journal of Nutrition, 141, 1165–1171. 50. Wang, X., Zhu, H., Snieder, H., Su, S., Munn, D., Harshfield, G., et al. (2010). Obesity related methylation changes in DNA of peripheral blood leukocytes. BMC Medicine, 8, 87. 51. Zhang, F. F., Cardarelli, R., Zhang, F. F., Carroll, J., Fulda, K. G., Gonzalez, K., et al. (2011). Physical activity and global genomic DNA methylation in a cancer-free population. Epigenetics, 6, 293–299. 52. Van der Auwera, I., Elst, H. J., Van Laere, S. J., Maes, H., Huget, P., van Dam, P., et al. (2009). The presence of circulating total DNA and methylated genes is associated with circulationg tumour cells in blood from breast cancer patients. British Journal of Cancer, 100, 1277–1286. 53. Yazici, H., Terry, M. B., Cho, Y. H., Senie, R. T., Liao, Y., Andrulis, I., et al. Aberrant methylation of RASSFIA in plasma DNA before breast cancer diagnosis in the Breast Cancer Family Registry. 54. Wang, Y. C., Yu, Z. H., Lio, C., Xu, L. Z., Yu, W., Lu, J., et al. (2008). Detection of RASSFIA promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients. World Journal of Gastroenterology, 14, 3074–3080. 55. Ellinger, J., Haan, K., Heukamp, L. C., Kahl, P., Meller, S. C., et al. (2008). CpG island hypermethylation in cell-free serum DNA identifies patients with localized prostate cancer. Prostate, 68, 42–49. 56. Lofton-Day, C., Model, F., Devos, T., Tetzner, R., Distler, J., Schuster, M., et al. (2008). DNA Methylation biomarkers for blood-based colorectal cancer screening. Clinical Chemistry, 54, 414–423. 57. Gobel, G., Auer, D., Gaugg, I., Schneitter, A., Lesche, R., Muller-Holzner, E., et al. (2011). Prognostic significance of methylated RASSFIA and PITX2 genes in blood—and bone


58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

marrow plasma of breast cancer patients. Breast Cancer Research and Treatment, 130(1), 109–117. Sunami, E., Shinozaki, M., Higano, C. S., Wollman, R., Dorff, T. B., Tucker, S. J., et al. (2009). Multimarker circulating DNA assay for assessing blood of prostate cancer patients. Clinical Chemistry, 55, 559–567. Lee, B. B., Lee, E. J., Jung, E. H., Chun, H. K., Chang, D. K., Song, S. Y., et al. (2009). Aberrant methylation of APC, MGMT, RASSF2A, and Wif-l genes in plasma as a biomarker for early detection of colorectal cancer. Clinical Cancer Research, 15, 6185–6191. Kaaks, R., Stattin, P., Villar, S., Poetsch, A. R., Dossus, L., Nieters, A., et al. (2009). Insulin-like growth factor-II methylation status in lymphocyte DNA colon cancer risk in the Northern Sweden health and disease cohort. Cancer Research, 69, 5400–5405. Cash, H. L., Tao, L., Yuan, J. M., Marsit, C. J., Houseman, E. A., Xiang, Y. B., et al. (2012). LINE-l hypomethylation is associated with bladder cancer risk among non-smoking Chinese. International Journal of Cancer, 130(5), 1151–1159. Wang, L., Aakre, J. A., Jiang, R., Marks, R. S., Eu, Y., Chen, J., et al. (2010). Methylation markers for small cell lung cancer in peripheral blood leukocyte DNA. Journal of Thoracic Oncology, 5, 778–785. Al-Moundhri, M. S., Al-Nabhani, M., Tarantini, L., Baccarelli, A., & Rusiecki, J. A. (2010). The prognostic significance of whole blood global and specific DNA methylation levels in gastric adenocarcinoma. PLoS ONE, 5, e15585. Tierling, S., Schuster, M., Tetzner, R., & Walter, J. (2010). A combined HM-PCR/SNuPE method for high sensitive detection of rare DNA methylation. Epigenetics and Chromatin, 3, 12. Radpour, R., Barekati, Z., Kohler, C., Lv, Q., Burki, N., Diesch, C., et al. (2011). Hypermethylation of tumor suppressor genes involved in critical regulatory pathways for developing a bloodbased test in breast cancer. PLoS ONE, 6, e16080. De Vos, T., Tetzner, R., Model, F., Weiss, G., Schuster, M., Distler, J., et al. (2009). Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. Clinical Chemistry, 55, 1337–1346. Melnikov, A. A., Scholtens, D., Talamonti, M. S., Bentrem, D. J., & Levenson, V. V. (2009). Methylation profile of circulating plasma DNA in patients with pancreatic cancer. Journal of Surgical Oncology, 99, 119–122. Cho, Y. H., Yazici, H., Wu, H. C., Terry, M. B., Gonzalez, K., Qu, M., et al. (2010). Aberrant promoter hypermethylation and genomic hypomethylation in tumor, adjacent normal tissues and blood from breast cancer patients. Anticancer Research, 30, 2489–2496. Wilhelm, C. S., Kelsey, K. T., Butler, R., Plaza, S., Zens, M. S., et al. (2010). Implications of LINE1 methylation for bladder cancer risk in women. Clinical Cancer Research, 16, 1682– 1689. Pinheiro, H., Bordeira-Carrico, R., Seixas, S., Carvalho, J., Senz, J., Oliveira, P., et al. (2010). Allele-specific CDHl downregulation and hereditary diffuse gastric cancer. Human Molecular Genetics, 19, 943–952. Wilson, A. S., Power, B. E., & Molloy, P. L. (2007). DNA hypomethylation and human diseases. Biochimica et Biophysica Acta, 1775(1), 138–162. Paredes, J., Albergaria, A., Oliveira, J. T., Jeronimo, C., Milanezi, F., & Schmitt, F. C. (2005). P-cadherin overexpression is an indicator of clinical outcome in invasive breast carcinomas and is associated with CDH3 promoter hypomethylation. Clinical Cancer Research, 11(16), 5869–5877.

511 73. Liu, H., Liu, W., Eu, Y., et al. (2005). Loss of epigenetic control of synuclein-c as a molecular indicator of metastasis in a wide range of human cancers. Cancer Research, 65(17), 7635–7643. 74. Woodson, K., Mason, J., Choi, S. W., et al. (2001). Hypomethylation of p53 in peripheral blood DNA is associated with the development of lung cancer. Cancer Epidemiology, Biomarkers and Prevention, 10(1), 69–74. 75. Callinan, P. A., & Feinberg, A. P. (2006). The emerging science of epigenomics. Human Molecular Genetics, 15(Spec. No.1), R95–R101. 76. Yang, A. S., Estecio, M. R., Doshi, K., Kondo, Y., Tajara, E. H., & Issa, J. P. (2004). A simple method for edtrimating global DNA methylation using bisulfit PCR of repetitive DNA elements. Nucleic Acids Research, 32(3), e38. 77. Ogino, S., Nosho, K., Kirkner, G. J., et al. (2008). A cohort study of tumoral line-1 hypomethylation and prognosis in colon cancer. Journal National Cancer Institute, 100(23), 1734–1738. 78. Irahara, N., Nosho, K., Baba, Y., et al. (2010). Precision of pyrosequencing assay to measure lin-1 methylation in colon cancer, normal colonic mucosa, and peripheral blood cells. The Journal of Molecular Diagnostics, 12(2), 177–183. 79. Lee, Y., Ahn, C., Han, H., et al. (2003). The nuclear RNase III drosha initiates micron processing. Nature, 425(6956), 415–419. 80. Lund, E., Guttinger, S., Calado, A., et al. (2004). Nuclear export of micron precursors. Science, 303(5654), 95–98. 81. Nilsen, T. W. (2007). Mechanisms of micron-mediated gene regulation in animal cells. Trends of Genetics, 23(5), 243–249. 82. Wiemer, E. A. (2007). The role of micronas in cancer: no small matter. European Journal of Cancer, 43(10), 1529–1544. 83. Michael, M. Z., SM, O. C., van Holst Pellekaan, N. G., et al. (2003). Reduced accumulation of specific micronas in colorectal neoplasia. Cancer Research, 1(12), 882–891. 84. Kitade, Y., & Akao, Y. (2010). Micronas and their therapeutic potential for human diseases micronas, mir-143 and -145 function as anti-oncomirs and the application of chemically modified mir143 as an anti-cancer drug. Journal of Pharmacology Science, 114(3), 276–280. 85. Ng, E. K., Chong, W. W., Jin, H., et al. (2009). Differential expression of micronas in plasma of patients with colorectal cancer: A potential marker for colorectal cancer screening. Gut, 58(10), 1375–1381. 86. Koga, Y., Yasunaga, M., & Takahashi, A. (2010). Microna expression profiling of exfoliated colonocytes isolated from feces for colorectal cancer screening. Cancer Prevention Research (Philadelphia, Pa.), 3(11), 1435–1442. 87. Lagos-Quintana, M., Rauhut, R., Lendeckel, W., et al. (2001). Identification of novel genes coding for small expressed rnas. Science, 294(5543), 853–858. 88. Wang, C. J., Zhoi, Z. G., Wang, L., et al. (2009). Clinicopathological significance of micronas-31,-143 and -145 expression in colorectal cancer. Disease Markers, 26(1), 27–34. 89. Slaby, O., Svoboda, M., Fabian, P., et al. (2007). Altered expression of mir-21, mir-31, mir-143 and mir-145 is related to cliniccopathologic features of colorectal cancer [J]. Oncology, 72(5–6), 397–402. 90. Wang, C. J., Stratmann, J., Zhou, Z. G., et al. (2010). Suppression of micron-31 increases sensitivity to 5-FU at an early stage, and affects cell migration and invasion in HCT-116colon cancer cells. BMC Cancer, 10, 616. 91. Cheng, H., Zhang, L., Cogdell, D. E., et al. (2011). Circulating plasma mir-141 is a novel biomarker for metastatic colon cancer and predicts poor prognosis. PLoS ONE, 6(3), e17745. 92. Schepeler, T., Reinert, J. T., Ostenfeld, M. S., et al. (2008). Diagnostic and prognostic micronas in stage II colon cancer. Cancer Research, 68(15), 6414–6424.

123

512 93. Schetter, A. J., Leung, S. Y., Sohn, J. J., et al. (2008). Microna expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA, 299(4), 425–436. 94. Volinia, S., Calin, G. A., Liu, C. G., et al. (2006). A micron expression signature of human solid tumors defines cancer gene targets [J]. Proceedings of the National Academy of Sciences of the United States of America, 103(7), 2257–2261. 95. Longley, D. B., Harkin, D. P., & Johnston, P. G. (2003). 5-fluorouracil: Mechanisms of action and clinical strategies. Nature Review Cancer, 3(5), 330–338. 96. Schetter, A. J., Nguyen, G. H., Bowmen, E. D., et al. (2009). Association of inflammation-related and micron gene expression with cancer-specific mortality of colon adenocarcinoma. Clinical Cancer Research, 15(18), 5878–5887. 97. Bandres, E., Agirre, X., Bitarte, N., et al. (2009). Epigenetic regulation of micron expression in colorectal cancer. International Journal of Cancer, 125(11), 2737–2743. 98. Balaguer, F., Link, A., Lozano, J. J., et al. (2010). Epigenetic silencing of mir-137 is an early event in colorectal carcinogenesis. Cancer Research, 70(16), 6609–6618. 99. Saito, Y., Liang, G., Egger, G., et al. (2006). Specific activation of microrna-127 with downregulation of the protooncogene bcl6 by chromatin-modifying drugs in human cancer cells. Cancer Cell, 9(6), 435–443. 100. Lujambio, A., Ropero, S., Ballestar, E., et al. (2007). Genetic unmasking of an epigenetically silenced microrna in human cancer cells [J]. Cancer Research, 67(4), 1424–1429. 101. Berger, S. L. (2002). Histone modifications in transcriptional regulation. Current Opinion in Genetics & Development, 12(2), 142–148. 102. Barski, A., Cuddapah, S., Cui, K., et al. (2007). High-resolution profiling of histone methylations in the human genome. Cell, 129(4), 823–837. 103. Litt, M. D., Simpson, M., Gaszner, M., et al. (2001). Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus [J]. Science, 293(5539), 2453–2455. 104. Noma, L., Allis, C. D., & Grewal, Sl. (2001). Transitions in distinct histone H3 methylation patterns at the heterochromatin domain boundaries. Science, 293(5532), 1150–1155. 105. Richon, V. M., Sandhof, T. W., Rifkind, R. A., et al. (2000). Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proceedings of the National Academy of Sciences of the United States of America, 97(18), 10014–10019. 106. Pruitt, K., Zinn, R. L., Ohm, J. E., et al. (2006). Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genetics, 2(3), e40. 107. Tsang, D. P. F., & Cheng, A. S. L. (2011). Epigenetic regulation of signaling pathways in cancer: Role of the histone methyltransferase EZH2. Journal of Gastroenterolhepatology, 26(1), 19–27. 108. Pelaez, I. M., Kalogeropoulou, M., Ferraro, A., et al. (2010). Oncogenic ras alters the global and gene-specific histone modification pattern during epithelial-mesenchymal transition in colorectal carcinoma during epithelial-mesenchymal transition in colorectal carcinoma cells. Biology International, 42(6), 911–920. 109. Baylin, S. B., & Herman, J. G. (2000). DNA hypermethylation in tumorigenesis: Epigenetics joins [J]. Trends Genetics, 16(4), 168–174. 110. Jones, P. A., & Laird, P. (1999). Cancer epigenetics comes of age. Nature Genetics, 21(2), 163–167.

123

Cell Biochem Biophys (2013) 67:501–513 111. Jenuwein, T., & Allis, C. D. (2001). Translating the histone code. Science, 293(5532), 1074–1080. 112. Tamaru, H., & Selkar, E. R. (2001). A histone H3 methyltransferase controls DNA methylation in neurosporacrassa. Nature, 414(6861), 277–283. 113. Jackson, J. P., Lindroth, A. M., Cao, X., et al. (2002). Control of cpnpg DNA methylation by the kryptonite histone H3 methyltransferase. Nature, 416(6880), 558–560. 114. Herman, J. G., Umar, A., Polyak, K., et al. (1998). Incidence and functional consequences of HMLH promoter hypermethylation in colorectal carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 95(12), 6870–6875. 115. Farhrner, J. A., Eguchi, S., Herman, J. G., et al. (2002). Dependence of histone modification and gene expression on DNA hypermethylation in cancer. Cancer Research, 62(24), 7213–7218. 116. Valenzuela, M. T., Galisteo, R., Zuluaga, A., Villalobos, M., Nunez, M, I., Oliver, F. J., et al. (2002). Assessing the use of p16INK4a promoter gene methylation in serum for detection of bladder cancer. European Urology 42: 622–628, discussion 628–630. 117. Leung, W. K., To, K. F., Chu, E. S., Chan, M. W., Bai, A. H., Ng, E. K., et al. (2005). Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer. British Journal of Cancer, 92, 2190–2194. 118. Wong, T. S., Man, M. W., Lam, A. K., Wei, W. I., Kwong, Y. L., & Yuen, A. P. (2003). The study of p16 and p15 gene methylation in head and neck squamous cell carcinoma and their quantitative evaluation in plasma by real-time PCR. European Journal of Cancer, 39, 1881–1887. 119. Fujiwara, K., Fujimoto, N., Tabata, M., Nishii, K., Matsuo, K., Hotta, K., et al. (2005). Identification of epigenetic aberrant promoter methylation in serum DNA is useful for early detection of lung cancer. Clinical Cancer Research, 11, 1219–1225. 120. Wong, T. S., Kwong, D. L., Sham, J. S., Wei, W. I., Kwong, Y. L., & Yuen, A. P. (2004). Quantitative plasma hypermethylation DNA markers of undifferentiated nasopharyngeal carcinoma. Clinical Cancer Research, 10, 2401–2406. 121. Reibenwein, J., Pils, D., Horak, P., Tomicek, B., Goldner, G., Worel, N., et al. (2007). Promoter hypermethylation of GSTPI, AR, and 14-3-3 sigma in serum of prostate cancer patients and is clinical relevance. Prostate, 67, 427–432. 122. Fiegl, H., Millinger, S., Mueller-Holzner, E., Marth, C., Ensinger, C., Berger, A., et al. (2005). Circulating tumor-specific DNA: A marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Research, 65, 1141–1145. 123. Muller, H. M., Widschwendter, A., Fiegl, H., Ivarsson, L. M., Goebel, G., Perkmann, E., et al. (2003). DNA methylation in serum of breast cancer patients: An independents prognostic marker. Cancer Research, 63, 7641–7645. 124. Dominguez, G., Carballido, J., Silva, J., Silva, J. M., Garcia, J. M., Menendez, J., et al. (2002). p14ARF promoter hypermethylation in plasma DNA as an indicator of disease recurrence in bladder cancer patients. Clinical Cancer Research, 5, 980–985. 125. Widschwendter, A., Muller, H. M., Fiegl, H., Ivarsson, L., Wirdemair, A., Muller-Holzner, E., et al. (2004). DNA methylation in serum and tumors of cervical cancer patients. Clinical Cancer Research, 10, 565–571. 126. Widschwendter, A., Ivarsson, L., Blassnig, A., Muller, H. M., Fiegl, H., Wiedemair, A., et al. (2004). CDH1 and CDH13 methylation in serum is an independent prognostic marker in cervical cancer patients. International Journal of Cancer, 109, 163–166.

Cell Biochem Biophys (2013) 67:501–513 127. Wallner, M., Herbst, A., Behrens, A., Crispin, A., Stieber, P., Goke, B., et al. (2006). Methylation of serum DNA is an independent prognostic marker in colorectal cancer. Clinical Cancer Research, 12, 7347–7352. 128. Hoffmann, A. C., Kaifi, J. T., Vallbohmer, D., Yekebas, E., Grimminger, P., Leers, J. M., et al. (2009). Lack of prognostic significance of serum DNA methylation of DAPK, MGMT, and GSTPI in patients with non-small cell lung cancer. Journal of Surgical Oncology, 100, 414–417. 129. Kawakami, K., Brabender, J., Lord, R. V., Groshen, S., Greenwaid, B. D., Krasna, M. J., et al. (2000). Hypermethylation APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. Journal of National Cancer Research, 92, 1805–1811. 130. Tangkijvanich, P., Hourpai, N., Rattanatanyong, P., Wisedopas, N., Mahachai, V., & Multirangura, A. (2007). Serum LINE-1 hypomethylation as a potential prognostic marker for hepatocellular carcinoma. Clinical Cancer Acta, 379, 127–133. 131. Ramirez, J. L., Rosell, R., Taron, M., Sanchez-Ronco, M., Alberola, V., Las de Penas, R., et al. (2005). 14-3-3 {sigma}methylation in pretreatment serum circulating DNA of

513

132.

133.

134.

135.

cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: The Spanish Lung Cancer Group. Journal of Clinical Oncology, 23, 9105–9112. Gifford, G., Paul, J., Vasey, P. A., Kaye, S. B., & Brown, R. (2004). The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clinical Cancer Research, 10, 4420–4426. Bastian, P. J., Palapattu, G. S., Lin, X., Yegnasubrammanian, S., Mangold, L. A., Trock, B., et al. (2005). Preoperative serum DNA GSTPI CpG island hypermethylation and the risk of early prostatic-specific antigen recurrence following radical prostatectomy. Clinical Cancer Research, 11, 4037–4043. Hoque, M. O., Feng, Q., Toure, P., Dem, A., Critchlow, C. W., Hawes, S. E., et al. (2006). Detection of aberrant methylation of four genes in plasma DNA for the detection of breast cancer. Journal of Clinical Oncology, 24, 4262–4269. Zhang, Y. J., Wu, H. C., Shen, J., Ahsan, H., Tsai, W. Y., Yang, H. I., et al. (2007). Predicting hepatocellular carcinoma by detection of aberrant promoter methylation in serum DNA. Clinical Cancer Research, 13, 2378–2384.

123