Abstract
Dnmt1 is frequently overexpressed in cancers, which contributes significantly to cancer-associated epigenetic silencing of tumor suppressor genes. However, the mechanism of Dnmt1 overexpression remains elusive. Herein, we elucidate a pathway through which nuclear receptor SHP inhibits zinc-dependent induction of Dnmt1 by antagonizing metal-responsive transcription factor-1 (MTF-1). Zinc treatment induces Dnmt1 transcription by increasing the occupancy of MTF-1 on the Dnmt1 promoter while decreasing SHP expression. SHP in turn represses MTF-1 expression and abolishes zinc-mediated changes in the chromatin configuration of the Dnmt1 promoter. Dnmt1 expression is increased in SHP-knockout (sko) mice but decreased in SHP-transgenic (stg) mice. In human hepatocellular carcinoma (HCC), increased DNMT1 expression is negatively correlated with SHP levels. Our study provides a molecular explanation for increased Dnmt1 expression in HCC and highlights SHP as a potential therapeutic target.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Carcinoma, Hepatocellular / enzymology
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Carcinoma, Hepatocellular / genetics*
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Cell Line
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Cell Line, Tumor
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / biosynthesis
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DNA (Cytosine-5-)-Methyltransferases / genetics*
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation, Enzymologic
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Gene Expression Regulation, Neoplastic
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Hepatocytes / enzymology
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Humans
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Liver / enzymology
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Liver Neoplasms / enzymology
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Liver Neoplasms / genetics*
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Mice
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Mice, Knockout
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Mice, Transgenic
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Repressor Proteins / metabolism*
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Transcription Factor MTF-1
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Transcription, Genetic / drug effects
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Zinc / pharmacology*
Substances
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DNA-Binding Proteins
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Receptors, Cytoplasmic and Nuclear
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Repressor Proteins
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Transcription Factors
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nuclear receptor subfamily 0, group B, member 2
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNMT1 protein, human
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Dnmt1 protein, mouse
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Zinc