2 - DNA Methylation and Cancer
Introduction
To establish an organism, classical genetic processes are not sufficient. For proper development and cell functioning, the epigenetic phenomena are absolutely required, controlling gene expression. Epigenetic could be defined as study of heritable changes in gene expression that occur independently of changes in primary DNA sequence. Distinct epigenomes may explain differences in cell state during development when zygote transforms to somatic tissue, even if the DNA stays the same. It seems also logic that epigenetic correlates with several diseases, that has been proved in monozygotic twins that are sharing exactly the same genetic material but not necessarily the same epigenome (Fraga et al., 2005).
Epigenetic regulation of gene expression is mediated by mechanisms such as methylation of DNA, modifications of histones, and positioning of nucleosome along the DNA. The interplay between epigenetic components guarantees proper balance between transcriptional activity and repression by changing chromatin architecture. Thus, regulation of packaging of DNA ensures maintenance of correct chromosome replication, gene expression, and stable gene silencing (Esteller, 2007). DNA methylation is one of the most intensely studied epigenetic modifications in mammals and it has an important impact on normal cell physiology. As this DNA modification seems to be a critical player in the transcriptional regulation, it is not surprising that defects in this mechanism may lead to various diseases, including cancer (Esteller, 2008). Indeed, in 1983 Feinberg and Vogelstein observed reduction of DNA methylation of specific genes in human colon cancer cells, comparing with normal tissues (Feinberg and Vogelstein, 1983). In the same year, Gama-Sosa et al. described a global reduction of 5-methylcytosine content of DNA from tumor samples (Gama-Sosa et al., 1983). Since these findings, being the first proof of molecular epigenetic abnormalities in cancer, we have significantly broadened our knowledge in that field (Esteller, 2008). Even if there is still far less known about epigenetic inheritance system and mechanisms of action than traditional genetics, the importance of DNA methylation in carcinogenesis is beyond any doubt.
In this chapter, we will try to summarize our actual state of knowledge concerning DNA methylation alteration in tumor progression.
Section snippets
The Molecular Basis of DNA Methylation
The propagation of DNA methylation is well understood at the biochemical level. It consists of the covalent addition of a methyl group (–CH3) that occurs exclusively at the 5 position of the cytosine moiety (Fig. 2.1A). Intriguingly, methylated cytosine could be converted into 5-hydroxymethylcytosine (hmC), structurally similar to its unmodified counterpart (Tahiliani et al., 2009). This kind of modification was found in cerebellar Purkinje neurons and in embryonic stem cells but the biological
DNA Methylation Abnormalities in Cancer
Appropriate DNA methylation is essential for development and proper cell functioning, thus any abnormalities in this process may lead to various diseases, including cancer. Indeed, tumor cells are characterized by a different methylome from that of normal cells. Interestingly, both hypo- and hypermethylation events can be observed in cancer. Generally, a global decrease in methylated CpG content is observed. This phenomenon contributes to genomic instability and, less frequently, to activation
DNA Methylation Markers
Despite our constantly growing understanding of carcinogenesis, there is still an eager needs to design novel, powerful tools that can be applied as part of clinical practice. Tumor biomarkers are indispensable not only for early diagnosis of cancer but also for prognosis, prediction of therapeutic response, monitoring therapy, or assessment of risk of recurrence after curative surgery. Many different molecules, including nucleic acids, proteins, or even small metabolites, could be used as the
Determining the Cancer DNA Methylome
The importance of DNA methylation alterations in tumorigenesis encourages us to decode the human epigenome. Nowadays, various methods are available to assess the DNA methylation pattern of particular DNA regions. Important progress has also been made toward completing a large-scale analysis of DNA methylation.
5-Methylcytosines can be detected by three possible methods based on (1) bisulfite conversion of DNA, (2) methyl-sensitive restriction enzymes, or (3) chromatin immunoprecipitation (ChIP)
Therapy Perspectives
Unlike genetic alterations, epigenetic events, including DNA methylation, are reversible, which makes it extremely interesting from the point of view of developing new approaches to therapy. The agents capable of restoring the normal cell DNA methylation pattern have been developed in the course of several studies. The strategies use special drugs to inactivate DNMTs. As an expected result of this approach, DNMT inhibitors should trigger the loss of the overall level that is thought to randomly
Conclusions
Since its discovery, DNA methylation has captured a lot of interest and its fundamental role in proper cell functioning is broadly recognized. Numerous studies have shown the key role of DNA methylation in tumor development and progression. Particularly, promoter hypermethylation resulting in gene silencing is one of the central players in cancer. In addition to classical genetic abnormalities, DNA methylation aberrations are considered as a second layer of tumorigenesis complexicity. Moreover,
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