title: Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP.
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.
authors.affiliation: Department of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhang
authors.forename: Glen K
authors.initials: GK
authors.lastname: Andrews
authors.forename: Li
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology*; D000097809:Transcription Factor MTF-1
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D015032:Zinc; D000097809:Transcription Factor MTF-1; C099713:nuclear receptor subfamily 0, group B, member 2; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse