Transcriptional regulation of Wnt inhibitory factor-1 by Miz-1 c-Myc

The Wnt signaling pathway is capable of self-regulation through positive and negative feedback mechanisms. For example, the oncoprotein c-Myc, which is upregulated by Wnt signaling activity, participates in a positive feedback loop of canonical Wnt signaling through repression of Wnt antagonists DKK...

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Bibliographic Details
Published in:	Oncogene Vol. 29; no. 44; pp. 5923 - 5934
Main Authors:	Licchesi, J D F, Van Neste, L, Tiwari, V K, Cope, L, Lin, X, Baylin, S B, Herman, J G
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-11-2010 Nature Publishing Group
Subjects:	631/208/176/1988 631/337/176/2016 631/337/572 Adaptor Proteins, Signal Transducing - genetics Anopheles Antagonists Apoptosis Biological and medical sciences c-Myc protein Cancer Care and treatment Cell Biology Cell Line, Tumor Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular biology Chromatin Immunoprecipitation CpG islands Dkk1 protein DNA DNA Methylation Epigenetics Feedback Frizzled-related protein 1 Fundamental and applied biological sciences. Psychology Gene expression Gene Expression Regulation - physiology Gene mapping Gene regulation Gene Silencing Genetic aspects Genomes Human Genetics Humans Internal Medicine Kruppel-Like Transcription Factors - physiology Medicine Medicine & Public Health Methylation Molecular and cellular biology Molecular genetics Myc protein Oncology original-article Promoter Regions, Genetic Proteins Proto-Oncogene Proteins c-myc - physiology Repressor Proteins - genetics Reverse Transcriptase Polymerase Chain Reaction Signal transduction Transcription, Genetic - physiology Transcription. Transcription factor. Splicing. Rna processing Wnt protein DNA methylation Wnt signaling Miz-1 c-Myc Transcription Carcinogenesis Cell signaling Signal transduction Regulation(control) WIF-1 DNA C-Onc gene Methylation Protooncogene
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Summary:	The Wnt signaling pathway is capable of self-regulation through positive and negative feedback mechanisms. For example, the oncoprotein c-Myc, which is upregulated by Wnt signaling activity, participates in a positive feedback loop of canonical Wnt signaling through repression of Wnt antagonists DKK1 and SFRP1 . In this study, we investigated the mechanism of Wnt inhibitory factor-1 ( WIF-1 ) silencing. Mapping of CpG island methylation of the WIF-1 promoter reveals regional methylation (−295 to −95 bp from the transcription start site) that correlates with transcriptional silencing. We identified Miz-1 as a direct activator of WIF-1 transcriptional activity, which is found at WIF-1 promoter. In addition, we show that c-Myc contributes to WIF-1 transcriptional repression in a Miz-1-dependent manner. Although the transient repression mediated by Miz-1/c-Myc is independent of de novo methylation, the stable repression by this complex is associated with CpG island methylation of the critical −295 to −95-bp region of the WIF-1 promoter. Importantly, Miz-1 and c-Myc are found at WIF-1 promoter in WIF-1 non-expressing cell lines DLD-1 and 209 myc . Transient knockdown or somatic knockout of c-Myc in DLD-1 failed to restore WIF-1 expression suggesting that c-Myc is involved in initiating rather than maintaining WIF-1 epigenetic silencing. In a genome-wide screen, DNAJA4 , TGFβ-induced and TRIM59 were repressed by c-Myc overexpression and DNA promoter hypermethylation. Our data reveal novel insights into c-Myc-mediated DNA methylation-dependent transcriptional silencing, a mechanism that might contribute to the dysregulation of Wnt signaling in cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2010.322