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

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 t...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2002-12, Vol.62 (24), p.7213-7218
Main Authors: FAHRNER, Jill A, EGUCHI, Sayaka, HERMAN, James G, BAYLIN, Stephen B
Format: Article
Language:English
Subjects:
Acetylation
Adaptor Proteins, Signal Transducing
Azacitidine - analogs & derivatives
Azacitidine - pharmacology
Biological and medical sciences
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
Medical sciences
Methylation
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
MutL Protein Homolog 1
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Nuclear Proteins
Promoter Regions, Genetic
Transcription, Genetic - drug effects
Transcription, Genetic - genetics
Tumor Cells, Cultured
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445