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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Dependence of histone modifications and gene expression on DNA hypermethylation in cancer.

Authors: Fahrner, Jill A; Eguchi, Sayaka; Herman, James G; Baylin, Stephen B

Published In Cancer Res, (2002 Dec 15)

Abstract: We examined the relationship between aberrant DNA hypermethylation and key histone code components at a hypermethylated, silenced tumor suppressor gene promoter in human cancer. In lower eukaryotes, methylated H3-lysine 9 (methyl-H3-K9) determines DNA methylation and correlates with repressed gene transcription. Here we show that a zone of deacetylated histone H3 plus methyl-H3-K9 surrounds a hypermethylated, silenced hMLH1 promoter, which, when unmethylated and active, is embedded in methyl-H3-K4 and acetylated H3. Inhibiting DNA methyltransferases, but not histone deacetylases, leads first to promoter demethylation, second to gene reexpression, and finally to complete histone code reversal. Our findings suggest a new paradigm-DNA methylation may directly, or indirectly by inhibiting transcription, maintain key repressive elements of the histone code at a hypermethylated gene promoter in cancer.

PubMed ID: 12499261 Exiting the NIEHS site

MeSH Terms: Acetylation; Adaptor Proteins, Signal Transducing; Azacitidine/analogs & derivatives*; Azacitidine/pharmacology; Carrier Proteins; Colorectal Neoplasms/genetics; Colorectal Neoplasms/metabolism; DNA Methylation/drug effects; DNA Modification Methylases/antagonists & inhibitors; DNA Modification Methylases/metabolism; Gene Expression Regulation, Neoplastic/drug effects; Gene Expression Regulation, Neoplastic/genetics; Gene Silencing/physiology*; Histone Deacetylase Inhibitors; Histone Deacetylases/metabolism; Histones/genetics*; Histones/metabolism; Humans; Hydroxamic Acids/pharmacology; Methylation; Neoplasm Proteins/biosynthesis; Neoplasm Proteins/genetics; Nuclear Proteins; Promoter Regions, Genetic; Transcription, Genetic/drug effects; Transcription, Genetic/genetics; Tumor Cells, Cultured

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