Reversal of gene silencing as a therapeutic target for cancer - Roles for DNA methylation and its interdigitation with chromatin

It has become apparent over the past several years that one of the attractive emerging prevention and therapy targets for cancer is the reversal of aberrant gene silencing mediated by epigenetic events associated with transcriptional repression. Integral to the possibilities for this targeting is the need to dissect the molecular mechanisms which underlie these transcriptional changes. At present, the best studied of the epigenetically silenced genes involved in cancer are those which harbour aberrant DNA promoter region methylation. This growing list includes almost half of all proven tumour suppressor genes and also a rapidly expanding list of genes with candidate roles for antitumour activities as well. Thus, one approach receiving much attention for restoring expression of abnormally silenced cancer genes for therapeutic purposes is utilization of agents such as 5-azacytidine (5-AzaC) and 5′-deoxy-azacytidine (DAC), which inhibit the DNA methyltransferases (DNMTs) that catalyse DNA methylation. Other approaches, and particularly the notion of utilizing inhibitors of histone de-acetylation, are being suggested by the exploding body of data concerning the role of histone modifications in mediating gene expression status, and especially those parameters that participate in gene silencing. Importantly, these histone parameters, which arc the focus of this Novartis Foundation Symposium, are not only tightly linked to mechanisms through which DNA methylation participates in gene silencing, but are also being integrally linked to how abnormal patterns of this DNA modification may actually arise in tumour cells. In this brief review, it is hypothesized that these interactions between DNA methylation and histone modifications may have to be targeted to most effectively exploit the potential for using reversal of gene silencing as an approach to cancer prevention and treatment.