Abstract
DNA methylation alterations are now widely recognized as a contributing factor in human tumorigenesis. A significant number of tumor suppressor genes are transcriptionally silenced by promoter hypermethylation, and recent research implicates alterations in chromatin structure as the mechanistic basis for this repression. The enzymes responsible for catalyzing DNA-cytosine methylation, as well as the proteins involved in interpreting the DNA methylation signal, have now been elucidated. Technological advances, including gene expression microarrays and genome scanning techniques, have allowed the comprehensive measurement of DNA methylation changes in human cancers. An important distinction between DNA methylation (epigenetic) and mutation or deletion (genetic) tumor suppressor gene inactivation is that epigenetic inactivation can be abrogated by small molecules, including DNA methyltransferase and histone deacetylase inhibitors. Further, strategies have been developed that combine treatments with drugs that reactivate silenced gene expression with secondary agents that target the re-expressed genes and/or reconstituted signal transduction pathways. In this review, we will discuss in detail the mechanisms of gene silencing by DNA methylation, the techniques used to decipher the complement of methylation-inactivated genes in human cancers, and current and future strategies for reactivating the expression of methylation-silenced genes.
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Acknowledgements
We would like to thank the members of the Jones laboratory for valuable discussions and C Jette, B Karpf, B Moore and P Moos for critical reading of the manuscript. AR Karpf is a recipient of postdoctoral fellowship PF-99-151-01-CDD from the American Cancer Society. This work was supported by NIH P01-CA73992 (to DA Jones) and by the Huntsman Cancer Foundation.
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Karpf, A., Jones, D. Reactivating the expression of methylation silenced genes in human cancer. Oncogene 21, 5496–5503 (2002). https://doi.org/10.1038/sj.onc.1205602
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DOI: https://doi.org/10.1038/sj.onc.1205602
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