The fundamental role of epigenetic events in cancer

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Abstract
Tumour-related genes can be silenced by heritable epigenetic changes that involve DNA-methylation and chromatin-remodelling events. Epigenetic silencing should be regarded as one of the pathways that is necessary to satisfy Knudson's hypothesis that two hits are required for a phenotypic consequence of tumour-suppressor gene loss. Recent advances in the field of chromatin structure are beginning to link the 'histone code' with the DNA 'cytosine-methylation code', which indicates that these two processes are intimately linked. Methylated cytosine contributes directly to the genetic inactivation of tumour-suppressor genes by virtue of its enhanced mutability and by altering how cytosine residues interact with ultraviolet light and aromatic hydrocarbons. Cytosine methylation can also inactivate DNA-repair genes, therefore increasing the rate of mutagenesis. The mechanisms by which changes in DNA methylation are interpreted in normal and malignant cells are being deciphered rapidly. These alterations silence transcriptional initiation but do not block transcriptional elongation. The DNA-methyltransferase enzymes, which establish and maintain DNA-cytosine-methylation patterns, can also act as direct transcriptional repressors and interact with crucial chromatin-remodelling factors. These enzymes cooperate to maintain DNA-methylation patterns, and the roles of these multi-functional proteins are now beginning to be understood. DNA methylation and heterochromatin both have a propensity to spread from one region to another. This gradual spreading process can result in the permanent silencing of genes and presumably takes place when a breakdown occurs in the mechanisms that normally protect CpG islands from the DNA-methyltransferase enzymes. Genes that are silenced by inappropriate promoter hypermethylation can be relatively easily reactivated by treatment with DNA-methylation inhibitors, such as 5-aza nucleosides. New evidence shows that the activities of these inhibitors are enhanced by histone deacetylase inhibitors, which provides further evidence for a close interconnection between chromatin structure and DNA methylation. The altered methylation of CpG islands in DNA can be detected using highly sensitive techniques. This might allow for the development of new technologies to detect cancer cells and to provide prognostic information.