Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP
Copyright policy )Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP
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.
- Huntsman Cancer Institute United States
- University of Utah Health Care United States
- University of Utah United States
- UNIVERSITY OF UTAH
DNA (Cytosine-5-)-Methyltransferase 1, Mice, Knockout, Carcinoma, Hepatocellular, Transcription, Genetic, Liver Neoplasms, Receptors, Cytoplasmic and Nuclear, Mice, Transgenic, Gene Regulation, Chromatin and Epigenetics, Gene Expression Regulation, Enzymologic, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Repressor Proteins, Mice, Liver, Cell Line, Tumor, Hepatocytes, Animals, Humans, DNA (Cytosine-5-)-Methyltransferases, Transcription Factors
DNA (Cytosine-5-)-Methyltransferase 1, Mice, Knockout, Carcinoma, Hepatocellular, Transcription, Genetic, Liver Neoplasms, Receptors, Cytoplasmic and Nuclear, Mice, Transgenic, Gene Regulation, Chromatin and Epigenetics, Gene Expression Regulation, Enzymologic, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Repressor Proteins, Mice, Liver, Cell Line, Tumor, Hepatocytes, Animals, Humans, DNA (Cytosine-5-)-Methyltransferases, Transcription Factors
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