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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP
Yuxia Zhang1, Glen K Andrews, Li Wang
1Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Nucleic Acids Research
|February 25, 2012
Summary
Overexpressed DNA methyltransferase 1 (Dnmt1) drives cancer by silencing tumor suppressors. Nuclear receptor SHP inhibits Dnmt1 via metal-responsive transcription factor-1 (MTF-1), offering a potential therapeutic target for cancers like hepatocellular carcinoma (HCC).
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Mechanisms of Gene Regulation
Background:
- DNA methyltransferase 1 (Dnmt1) overexpression is common in cancers, leading to epigenetic silencing of tumor suppressor genes.
- The precise mechanisms driving Dnmt1 overexpression in cancer remain largely unknown.
Purpose of the Study:
- To elucidate the molecular pathway regulating Dnmt1 expression, focusing on the role of nuclear receptor SHP and its interaction with metal-responsive transcription factor-1 (MTF-1).
- To investigate the therapeutic potential of targeting SHP for controlling Dnmt1 levels in cancer, particularly hepatocellular carcinoma (HCC).
Main Methods:
- Investigated the interaction between SHP and MTF-1 in regulating Dnmt1 transcription.
- Utilized zinc treatment to modulate Dnmt1 and SHP expression, assessing MTF-1 occupancy on the Dnmt1 promoter.
- Examined Dnmt1 and SHP expression in SHP-knockout (sko) and SHP-transgenic (stg) mice.
- Correlated DNMT1 and SHP expression levels in human hepatocellular carcinoma (HCC) patient samples.
Main Results:
- Zinc treatment induces Dnmt1 transcription by enhancing MTF-1 binding to the Dnmt1 promoter and reducing SHP expression.
- SHP antagonizes MTF-1, repressing MTF-1 expression and preventing zinc-induced alterations in Dnmt1 promoter chromatin.
- Dnmt1 expression is elevated in SHP-knockout mice and reduced in SHP-transgenic mice.
- Increased DNMT1 expression in human HCC is inversely correlated with SHP levels.
Conclusions:
- SHP inhibits zinc-dependent Dnmt1 induction by antagonizing MTF-1, providing a molecular explanation for elevated Dnmt1 in HCC.
- SHP acts as a negative regulator of Dnmt1 expression, particularly in the context of zinc signaling.
- SHP represents a promising therapeutic target for managing Dnmt1 overexpression in cancers like HCC.
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