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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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Related in: MedlinePlus

Inverse correlation between DNMT1 and SHP mRNAs in human HCC. (A) qPCR analysis of DNMT1 and SHP mRNAs in 14 pairs of human HCC specimens (HCC) and their corresponding normal surrounding tissues (NT). The expression of DNMT1 and SHP in HCC was normalized to NT and the results were expressed as log 2. (B) Correlation between DNMT1 and SHP mRNA abundance in human HCC.
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gks159-F6: Inverse correlation between DNMT1 and SHP mRNAs in human HCC. (A) qPCR analysis of DNMT1 and SHP mRNAs in 14 pairs of human HCC specimens (HCC) and their corresponding normal surrounding tissues (NT). The expression of DNMT1 and SHP in HCC was normalized to NT and the results were expressed as log 2. (B) Correlation between DNMT1 and SHP mRNA abundance in human HCC.

Mentions: Our early studies reported decreased SHP mRNA due to promoter hypermethylation in human HCC specimens (19). Quantification of DNMT1 mRNA levels in 14 matched HCC specimens and paired non-neoplastic liver tissues (surrounding tissues) revealed elevated DNMT1 mRNA in a majority of these HCC (8/14) (Figure 6A). Increased DNMT1 mRNA negatively correlated with decreased SHP mRNA in HCC specimens (Figure 6B), consistent with a regulatory link between SHP and DNMT1 expression in HCC.Figure 6.


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

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

Inverse correlation between DNMT1 and SHP mRNAs in human HCC. (A) qPCR analysis of DNMT1 and SHP mRNAs in 14 pairs of human HCC specimens (HCC) and their corresponding normal surrounding tissues (NT). The expression of DNMT1 and SHP in HCC was normalized to NT and the results were expressed as log 2. (B) Correlation between DNMT1 and SHP mRNA abundance in human HCC.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

gks159-F6: Inverse correlation between DNMT1 and SHP mRNAs in human HCC. (A) qPCR analysis of DNMT1 and SHP mRNAs in 14 pairs of human HCC specimens (HCC) and their corresponding normal surrounding tissues (NT). The expression of DNMT1 and SHP in HCC was normalized to NT and the results were expressed as log 2. (B) Correlation between DNMT1 and SHP mRNA abundance in human HCC.
Mentions: Our early studies reported decreased SHP mRNA due to promoter hypermethylation in human HCC specimens (19). Quantification of DNMT1 mRNA levels in 14 matched HCC specimens and paired non-neoplastic liver tissues (surrounding tissues) revealed elevated DNMT1 mRNA in a majority of these HCC (8/14) (Figure 6A). Increased DNMT1 mRNA negatively correlated with decreased SHP mRNA in HCC specimens (Figure 6B), consistent with a regulatory link between SHP and DNMT1 expression in HCC.Figure 6.

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