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

Zhang Y, Andrews GK, Wang L - Nucleic Acids Res. (2012)

Bottom Line: SHP in turn represses MTF-1 expression and abolishes zinc-mediated changes in the chromatin configuration of the Dnmt1 promoter.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

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.

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Schematic showing SHP inhibition of the Dnmt1 promoter through two distinct mechanisms. Our recent study showed that SHP inhibits ERRγ transactivation of the Dnmt1 promoter. The present study identified a zinc-mediated induction of Dnmt1 which is modulated by the cross-inhibition between MTF-1 and SHP.
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gks159-F7: Schematic showing SHP inhibition of the Dnmt1 promoter through two distinct mechanisms. Our recent study showed that SHP inhibits ERRγ transactivation of the Dnmt1 promoter. The present study identified a zinc-mediated induction of Dnmt1 which is modulated by the cross-inhibition between MTF-1 and SHP.

Mentions: Recently we showed that SHP also inhibits Dnmt1 promoter transactivation by ERRγ in several cancer cells (29). The effect of SHP is through a direct protein–protein interaction with ERRγ to convert the local chromatin structure of the Dnmt1 promoter from a transcriptionally active mode to an inactive mode. Because SHP does not interact with the MTF-1 protein directly, SHP appears to repress Dnmt1 through decreasing MTF-1 expression. The induction of MTF-1 by zinc may activate Dnmt1 by repressing SHP, which represents a feed-forward inhibitory mechanism between SHP and MTF-1 that controls Dnmt1 expression. Thus, SHP modulates the expression of Dnmt1 by at least two distinct mechanisms (Figure 7).Figure 7.


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

Zhang Y, Andrews GK, Wang L - Nucleic Acids Res. (2012)

Schematic showing SHP inhibition of the Dnmt1 promoter through two distinct mechanisms. Our recent study showed that SHP inhibits ERRγ transactivation of the Dnmt1 promoter. The present study identified a zinc-mediated induction of Dnmt1 which is modulated by the cross-inhibition between MTF-1 and SHP.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367194&req=5

gks159-F7: Schematic showing SHP inhibition of the Dnmt1 promoter through two distinct mechanisms. Our recent study showed that SHP inhibits ERRγ transactivation of the Dnmt1 promoter. The present study identified a zinc-mediated induction of Dnmt1 which is modulated by the cross-inhibition between MTF-1 and SHP.
Mentions: Recently we showed that SHP also inhibits Dnmt1 promoter transactivation by ERRγ in several cancer cells (29). The effect of SHP is through a direct protein–protein interaction with ERRγ to convert the local chromatin structure of the Dnmt1 promoter from a transcriptionally active mode to an inactive mode. Because SHP does not interact with the MTF-1 protein directly, SHP appears to repress Dnmt1 through decreasing MTF-1 expression. The induction of MTF-1 by zinc may activate Dnmt1 by repressing SHP, which represents a feed-forward inhibitory mechanism between SHP and MTF-1 that controls Dnmt1 expression. Thus, SHP modulates the expression of Dnmt1 by at least two distinct mechanisms (Figure 7).Figure 7.

Bottom Line: SHP in turn represses MTF-1 expression and abolishes zinc-mediated changes in the chromatin configuration of the Dnmt1 promoter.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.

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.

Show MeSH
Related in: MedlinePlus