Reactivating the expression of methylation silenced genes in human cancer.
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.
Karpf
Adam R
AR
Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, Utah, UT 84112, USA. adam.karpf@hci.utah.edu
Jones
David A
DA
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004273:DNA, Neoplasm / Q000378:metabolism*; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy; D011401:Promoter Regions, Genetic
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine