Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP

Nucleic Acids Res. 2012 Jun;40(11):4850-60. doi: 10.1093/nar/gks159. Epub 2012 Feb 22.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics*
  • Cell Line
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / biosynthesis
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Hepatocytes / enzymology
  • Humans
  • Liver / enzymology
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Repressor Proteins / metabolism*
  • Transcription Factor MTF-1
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • Zinc / pharmacology*

Substances

  • DNA-Binding Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • Transcription Factors
  • nuclear receptor subfamily 0, group B, member 2
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Dnmt1 protein, mouse
  • Zinc