In vertebrate somatic cells, epigenetic regulation of gene expression reinforces stable expression states at different loci. These ''expression states'' are associated with particular molecular signatures of DNA and chromatin modifications that are characteristic of active or repressed genes. The end result is that differentiated cells have a restricted transcriptome profile and a limited developmental potential. In cancer cells, this regulatory mechanism is altered such that the transcriptome profile is changed to one that promotes cancer progression and maintenance. In cell lines, selection for rapid cell division can impose further epigenetic changes.
In general, cancer cells possess aberrant patterns of hypomethylation at repeat sequences and hypermethylation at the promoters of many genes (Baylin and Herman, 2000; Bjornsson et a/., 2004; Feinberg et a/., 2002; Feinberg and Tycko, 2004; Jones and Laird, 1999). This process can give the cell a selective growth advantage akin to mutation or gene loss. Decreases in this epigenetic modification of DNA in repetitive and parasitic elements can lead to expression of these elements and a decrease in genome stability. Hypermethylation, on the other hand, is less common but seems to prefer CpG sequences usually found in simple repeat sequences but also clustered (CpG island) in the promoter regions of genes (Goel et al., 2004; Kondo and Issa, 2004; Ricciardiello et a/., 2003). CpG island methylation is rare in normal cells and can repress transcription of the associated gene by recruiting MBDs and, in turn, repression complexes as detailed above (Ballestar et a/., 2003). A growing body of evidence implicates DNA methylation as an early mechanism in tumorigenesis. Promoter region hypermethylation of the retinoblastoma gene, responsible for the commonest ocular cancer in children, has in rare cases been detected in families affected by unilateral retinoblastoma (Ohtani-Fujita et a/., 1997). Additionally, studies of sporadic colon cancer have revealed increased methylation at the mismatch repair gene hMLHl. Downregulation of methylated hMLHl can be reversed upon treatment with the demethylating agent 5-azacytidine (Ricciardiello et a/., 2003). Such aberrant methylation events also fit into the Knudson two-hit model in the case of p16-INK4A, where one allele is mutated and nonfunctional with the other allele silenced by high levels of methylation (Myohanen et a/., 1998; Toyota et a/., 1999).
Epigenetic alterations in cancer are not uniform and are context-dependent. Previous studies have focused on hypermethylation and cancer, but it would be remiss to ignore decreased levels of this molecular mark, which may be of equal importance in establishing a transformed cell. A primary function of DNA methylation is to silence parasitic element transcription. In Dnmt1~'~ ES cells, transposable elements become demethylated and re-express (Walsh et a/., 1998). If this process is global, which it appears to be, the mobilization of transposable elements and insertion into a coding exon, transcription interference or generation of an antisense element, could be deleterious to cellular function and stability. Another threat posed by elements ''jumping about'' the genome is homologous recombination. A number of examples of repeat sequence recombination have been shown suggesting that DNA methylation can inhibit recombination and is required for genome stability (Chen et a/., 1998; Eden et a/., 2003; Gaudet et a/., 2003; Guo et a/., 2004). Consistent with this, murine Dnmt1~'~ ES cells exhibit a tenfold increased mutation rate involving gene rearrangements (Chen et a/., 1998). Mechanistically, how methylation of DNA suppresses homologous recombination events remains elusive, but a number of hypotheses have been offered to explain it including masking of the site of recombination; maintenance of a heterochromatic state; destabilization of the recombination intermediate; or direct interference with the recombination machinery.
A major breakthrough directly linking epige-netics and tumorigenesis was reported recently by Sansom et a/. who generated an MBD2 (methyl-binding domain protein 2) knockout mouse in an existing background of tumor susceptibility to test whether a reduced ability to interpret the DNA methylation signal might alter tumorigenesis (Sansom et a/., 2003). ApcMin/+ have multiple intestinal neoplasia modeled on the human cancer Familial Adenomatous Polyposis (FAP). Previous work had shown that MBD2_/~ mice are normal despite subtle behavioral peculiarities including improper maternal nurturing (Hendrich et a/., 2001). It was shown that APCMin/+ MBD2~/~ mice outlived control APCMln/+ mice and have ten times fewer adenomas. APCMin/+ MBD2+/~ survived for an intermediate amount of time indicating a dependence of tumor burden on the MBD2+ allele.
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