DNA methylation of mobile genetic elements in human cancers ...

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It is recently considered that the hypomethylation of mobile genetic elements may play a biological role in cancer cells along with the DNA hypermethylation on ...
Genes Genom (2013) 35:265–271 DOI 10.1007/s13258-013-0095-3

REVIEW

DNA methylation of mobile genetic elements in human cancers Kyudong Han • Jungname Lee • Heui-Soo Km Kwangmo Yang • Joo Mi Yi

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Received: 13 November 2012 / Accepted: 27 January 2013 / Published online: 14 February 2013 Ó The Genetics Society of Korea 2013

Abstract Mobile genetic elements are responsible for half of the human genome, creating the host genomic instability or variability through several mechanisms. Two types of abnormal DNA methylation in the genome, hypomethylation and hypermethylation, are associated with cancer progression. Genomic hypermethylation has been most often observed on the CpG islands around gene promoter regions in cancer cells. In contrast, hypomethylation has been observed on mobile genetic elements in the cancer cells. It is recently considered that the hypomethylation of mobile genetic elements may play a biological role in cancer cells along with the DNA hypermethylation on CpG islands. Growing evidence has indicated that mobile genetic elements could be associated with the cancer initiation and progression through the hypomethylation. Here we review the recent progress on the relationship between DNA methylation and mobile genetic elements, focusing on the hypomethylation of LINE-1 and HERV elements in various human cancers and suggest that DNA hypomethylation of mobile genetic elements could have potential to be a new cancer therapy target in the future.

K. Han  J. Lee Department of Nanobiomedical Science and WCU Research Center, Dankook University, Cheonan 330-714, South Korea H.-S. Km Department of Biological Science, Pusan National University, Busan 609-735, South Korea K. Yang  J. M. Yi (&) Research Institute, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Jwadong-gil 40, Jangan-eup, Gijang-gun, Busan, South Korea e-mail: [email protected]

Keywords Mobile genetic element  Hypermethylation  Hypomethylation  LINE elements  HERV elements

Introduction Mobile genetic elements, called junk DNAs or transposable elements, are present in the genome of all known eukaryotes. They account for at least 45 % of mammalian genomes (Gibbs et al. 2007; Gregory et al. 2002; Lander et al. 2001; Mikkelsen et al. 2005; Mills et al. 2011; Scally et al. 2012; Warren et al. 2008). The mobile genetic elements are classified into two major groups, according to their transposition mechanism, the first group is DNA transposon; this element moves into a new genomic region using ‘‘cut and paste’’ mechanism. The second group is retrotransposon; this element transcribes itself and then integrates into a new genomic region via reverse transcription of the RNA intermediates (‘‘copy and paste’’ mechanism). Thus, retrotransposons may well be more ubiquitous than DNA in the mammalian genomes. It has been reported that retrotransposons are capable of retrotransposition in various primate genomes and thus they have a major impact on the architecture and fluidity of their host genomes (Cordaux et al. 2006; Este´cio et al. 2010; Nekrutenko and Li 2001). Retrotransposons are divided into two groups, long terminal repeat (LTR) retrotransposons and non-LTR retrotransposons. Human endogenous retrovirus (HERV) is one of the LTR retrotransposons. In 1981, HERV was first characterized (Martin et al. 1981). It has been suggested that HERV was originated from exogenous retrovirus, inserted into its host genome during primate evolution because its gene structure is similar to that of exogenous retrovirus (50 LTR-gag-pol-env-30 LTR). However, unlike the exogenous virus, most open reading frames of HERV are not

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intact due to mutations such as deletion, insertion codons, and frame shift (Boeke and Stoye 1997; Lander et al. 2001; Stoye 2001). Nonetheless, it has been reported that some of HERVs are actively amplified in the human genome (Mayer and Meese 2005; Yi and Kim 2006; Yi et al 2007). In reality, previous studies about HERV showed that HERV mRNAs are differentially but universally expressed in various cell types and tissues (Yi et al. 2004, 2006, 2007) and HERV expression levels are various among individuals (Andersson et al. 1996). In addition, HERV proteins were found in cancer cells (Yi et al. 2006, 2007) as well as normal cells from placenta and embryo (Muir et al. 2004). In contrast, the LINE-1 elements belong to autonomous nonLTR retrotransposons. They account for approximately 17 % of the human genome (Lander et al. 2001). During the past 6 million years, about 2,000 copies of L1 elements newly inserted into the human genome and some of them are currently active to retrotranspose in the human genome (Beck et al. 2010; Brouha et al. 2003). Since the divergence of human and chimpanzee, L1s have modified the human genome through various mechanisms including de novo insertions, inversions, insertion-mediated deletions, and recombination events (Goodier et al. 2004; Han et al. 2005, 2008). Thus, L1 has acted as an agent causing human genomic variation and instability. Epigenetics is defined as heritable changes in gene expression that are not accompanied by changes in DNA sequence. The heritable changes include DNA methylation and histone modifications, which are now known to regulate a wide range of physiological and pathological processes (Jones and Baylin 2002). Gene silencing at the level of chromatin is necessary for eukaryotic organisms and is specifically important in biological processes, such as differentiation, imprinting, and silencing of large chromosomal domains including the X chromosome, over the life span of female mammals. Like most biological processes, the gene silencing can become dysregulated, resulting in the development of multiple disease states. Recently, there has been much emphasized on the critical role of DNA hypermethylation in human carcinogenesis (Herman and Baylin 2000; Issa 2000). In comparison with the hypermethylation, loss of DNA methylation in cancer has not been much considered in the field of cancer genomics. However, the extensive cancer-associated DNA hypomethylation in the human genome was discovered earlier than cancer-linked DNA hypermethylation (Feinberg and Vogelstein 1983). In cancer cells, DNA hypomethylation often has a higher effect on their genomes than does hypermethylation. As a result, net losses of genomic 5-methylcytosine were observed in many human cancers (Gama-Sosa et al. 1983). Therefore, here, we discuss mobile genetic elements associated with the DNA hypomethylation in cancer genomes and highlight their future clinical potential.

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DNA methylation in cancer DNA methylation is one of the important mechanisms that control gene expression, chromatin structure, genome stability and X-chromosome inactivation (Jones and Baylin 2002). Abnormal patterns of DNA methylation in cancer cells have been recognized for over 20 years. DNA methylation typically occurs at CpG sites, which are CG dinucleotide sequences that occur at a relatively low frequency in the genome (Herman and Baylin 2003). Mammalian DNA contains 5-methylcytosine, the genomic distribution of which is specific for each cell type and is largely established during embryonic development. Mammalian DNA methyltransferases recognize CpG dinucleotides at specific sites within the genome referred to as a ‘‘CpG island’’, a CpG-rich region often encompassing the promoter and transcription start site of the associated gene and possess de novo methylation activity (Bird 1986). Approximately half of all human genes contain CpG islands in the 50 area of their gene promoter (Bird 1986). DNA methylation patterns in normal tissues are in part dependent on the relative levels and activities of DNA methyltransferases and DNA demethylases whose expression is regulated at both the transcriptional and posttranscriptional level (Herman and Baylin 2003). Abnormal DNA methylation can lead to serious imbalance in normal function of cells and can promote pathological conditions. In particular, the cancer genome is known to undergo substantial changes in DNA methylation (Jones and Baylin 2002). Most notable are genome-wide hypomethylation events that preferentially target repetitive DNA elements, and gene-specific hypermethylation of CpG islands. Gene promoter DNA hypermethylation in cancer First classic tumor suppressor gene, the retinoblastoma gene (Rb), raised that DNA hypermethylation of Rb gene could be involved in gene inactivation in retinoblastoma. Sasaki and colleagues have described five retinoblastomas which contains tumor-specific hypermethylation in the promoter region (Sakai et al. 1991). Also, the von Hippel– Lindau gene (VHL) was cloned and shown to be responsible for the inherited syndrome, von Hippel–Lindau disease (Latif et al. 1993). Many groups have reported that VHL gene is associated with DNA promoter hypermethylation in renal cancer and hemangioblastoma (Clifford et al. 1998; Prowse et al. 1997). The most studied of all tumor suppressor genes for promoter hypermethylation is undoubtedly the p16 gene, currently designed CDKN2A, a cyclin-dependent kinase inhibitor which functions in the regulation of the phosphorylation status of the RB protein (Herman 1999). In fact, hypermethylation associated with the loss of

Genes Genom (2013) 35:265–271

Fig. 1 DNA methylation changes during cancer progression. Hypermethylation in CpG island promoter region of tumor suppressor genes induce gene silencing in cancers. In contrast, mobile genetic elements such as LINE-1 and HERV families showed hypomethylation in cancer therefore, lead to global genome instability. Recent evidences suggest that both cases could be contributed for causing human cancers. This schematic is simplified based on the DNA methylation levels in the genome. TSG indicates that tumor suppressor genes

expression of the CDKN2A gene has been found to be one of the most frequent alterations in neoplasia rather than homozygous deletion and some point mutations. First reports describe methylation of the p16 gene in lung, head and neck, gliomas, colorectal, and breast carcinomas (Herman et al. 1995; Merlo et al. 1995; Otterson et al. 1995). Another cyclin-dependent kinase inhibitor lies adjacent to CDKN2A on chromosome 9p21. This gene, p15 or CDKN2B, is structurally and functionally similar to CDKN2A in regulating the phosporylation of Rb. CDNK2B is frequently hypermethylated in many forms of hematological malignancies (Herman et al. 1997). Genes involved in DNA repair have also been founded to be frequently inactivated by promoter region hypermethylation in cancer. For example, methylation of GST-p, MGMT, and MLH1 gene has been found in various types of cancer along with loss of expression of these genes (Esteller et al. 1998; Kane et al. 1997; Qian and Brent 1997) (Fig. 1). Hypomethylation of LINE-1 in cancer Genome-wide DNA hypomethylation and gene-specific hypermethylation of CpG islands are prominent hallmarks of cancer genomes (Ehrlich 2002; Ushijima 2005). Aberrant DNA methylation can cause reactivation of methylationsilenced mobile genetic elements supposed to be methylated (inactive form), which result in increased genomic instability (Ehrlich 2002). Hypermethylation of mobile genetic elements such as LINE1, Alu, and some of HERV families, disperse across the genome in normal cells, but hypomethylation of mobile genetic element is frequently observed in cancers (Table 1). In reality, DNA hypomethylation is more pronounced in tumor progression or malignancy than normal cells (Ehrlich et al. 2006; Qu et al. 1999) although the pattern of the DNA hypomethylation is

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various, depending on cancer type and individual specimen (Jackson et al. 2004; Widschwendter et al. 2004). DNA hypomethylation of mobile genetic elements contributes to carcinogenesis and chromosomal rearrangements (Dobigny et al. 2004; Guz et al. 2010). Especially, DNA hypomethylation of mobile genetic elements located on centromeric and juxtacentromeric regions is associated with cervical neoplasia (Kim et al. 1994) and hepatocellular carcinoma (Shen et al. 1998). Therefore, it has been suggested that hypomethylations of interspersed repeats (e.g., LINE and SINE) and tandem repeats induce genomic rearrangements responsible for tumor formation or progression (Chen et al. 1998; Gaudet et al. 2003). Several studies have demonstrated that hypomethylation of LINE-1 is associated with cancers (Hoffmann and Schulz 2005; Ostertag and Kazazian 2001). Hypomethylated LINE-1s increase the copy number of their mRNAs and their reactivation can lead to transcriptional regulation of neighboring genes via transcriptional interference (Whitelaw and Martin 2001). Interestingly, being able to activate LINE-1 antisense promoter, hypomethylation of certain L1s is correlated with expression of alternative gene transcripts. In reality, it was reported that hypomethylation of a LINE-1 promoter creates alternative transcripts of the MET oncogene in bladder tumors. The L1-MET promoter was typically methylated in normal cells but most of the bladder carcinoma cell lines showed remarkable hypomethylation on the promoter (Wolff et al. 2010). Thus, the change in LINE-1 methylation level may be a useful marker when monitoring cancer progression. Low expression level of HERVs in various cancers A large and constantly growing number of reports have described detection of RNA transcripts from various HERV families in many different types of human cancers or tumor cell lines (Armbruester et al. 2002; Depil et al. 2002; Patzke et al. 2002; Wang-Johanning et al. 2003a, 2003b; Yi et al. 2004, 2006). Even though the detection of various HERV families transcripts in many cancer types, the biological significance of HERV RNA expression in cancers remains obscure. Specifically, one of class of human retrotransposons that is usually highly methylated and may become hypomethylated in association with carcinogenesis is the human endogenous retroviruses, especially, the HERV-K family. HERV-K family comprises 30–50 full length members per haploid genome, among which several contain intact open reading frames (Lo¨wer et al. 1996). HERV-K elements are the most intact among human endogenous retroviruses and make up 1–2 % of the human genome. Although, HERV-K sequences are relatively poor in CpG dinucleotides, for instance there are fewer than 20 in their LTRs, methylation of these

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268 Table 1 Hypomethylation of mobile genetic elements in different cancer types

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Type of cancer Breast cancer

Colorectal cancer

Gastric cancer Leukemia (chronic myelogenous leukemia) Lung cancer (non-small cell lung cancer) Melanoma

Prostate cancer

sequences like that of LINE-1 sequences may be important in controlling their ability to transcribed, to transpose and to participate in recombination. Expansion of our thoughts, we have tried to compare the expression pattern of various HERV families in different human tissues and cancer cell lines (Fig. 2). In human normal tissues, many HERV families have been expressed in human normal tissues (Fig. 2a) compared to various cancer cell lines (Fig. 2b). This gene expression profile of HERV families suggests that expression level of HERV families is losing their basal expression level in disease status such as cancers. As we mentioned earlier, lack of basal expression of genes could be implicated association with regulation by DNA methylation. In our gene expression profile in Fig. 2 could suggest that HERV elements might be regulated by DNA hypo or hypermethylation during cancer progression. However, expression of HERV proteins in tumor tissue provides an argument for some functional significances, some of crucial questions remain mainly how HERV protein expression could contribute to cancer development. Future perspective There is a poor understanding of the pathways that lead to cancer-associated hypomethylation of mobile genetic elements so far. Even though hypomethylation of mobile genetic elements is associated with cancer detection as a biomarker, little is known about biological roles for understanding human cancer. Evidence suggests that this

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Mobile genetic elements

References

HERV-W Env

Bjerregaard et al. 2006

Alu

Cho et al. 2010

LINE-1

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Chalitchagorn et al. (2004) and Ogino et al. (2008)

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hypomethylation of DNA in cancer is not a consequence of or a prelude to hypermethylation in cancer. The hypomethylation in repeated DNA sequences may play special roles in carcinogenesis, such as, increasing karyotype instability or affecting expression of genes indirectly. DNA hypermethylation has been known that it is emerging as an important diagnostic and prognostic tool. Like this, DNA hypomethylation analysis may also be useful in detecting cancer and managing the disease (Qu et al. 1999; Santourlidis et al. 1999; Shen et al. 1998). Yang et al. showed the changed in the methylation levels of the LINE-1 repetitive elements could be used as a surrogate marker of genomewide methylation changes (Yang et al. 2004). Also, LINE-1 and HERV-K sequences have been shown to be hypomethylated and transcribed in human teratocarcinoma cells (Bratthauer and Fanning 1992). Recently, the association of global or focal DNA hypomethylation with the early stages of carcinogenesis or with tumor progression provides cancer markers that should be very useful in the clinic (Compare et al. 2011). To discover new genome-wide hypomethylation locus or genes in cancer genome, high-throughput and high-resolution technology for DNA methylation analysis facilitated recently huge development for genome-wide analysis. Over the next 10 years, there will probably be many clinical tests in use that are based on biomarkers using DNA hypomethylation of mobile genetic elements for cancer detection and prognosis. Some type of cancer, DNA hypomethylation is seen as an early indicator of tumorigenesis (Feinberg and Vogelstein 1983). Take all by together, mobile genetic elements such as LINE or HERV

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Fig. 2 Gene expression profile of various HERV families in a human normal tissues and b cancer cell lines. X-axis shows different type of human normal tissues (a) and colon cancer cell lines (b). Y-axis

shows various HER families. Green color indicates HERVs have a basal expression in human normal tissues and cancer cell lines, but red color indicates no expression. (Color figure online)

families for DNA hypomethylation may become a clinically useful addition to hypermethylation analyses of CpG islands in human cancers and future studies should clarify this issue.

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Acknowledgments This work was supported in part by National R&D program (50596-2013) through the Dongnam Institute of Radiological & Medical Sciences (DIRAMS) funded by the Korean Ministry of Education, Science and Technology and by WCU (World Class University) program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R31-10069).

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