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

被引：0
作者：
J D F Licchesi
L Van Neste
V K Tiwari
L Cope
X Lin
S B Baylin
J G Herman
机构：
[1] Cancer Biology Program,Department of Molecular Biotechnology
[2] The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,Department of Applied Mathematics and Statistics
[3] MRC Laboratory of Molecular Biology,undefined
[4] Faculty of Bioscience Engineering,undefined
[5] Ghent University,undefined
[6] Whiting School of Engineering,undefined
[7] Johns Hopkins University,undefined
来源：
Oncogene | 2010年 / 29卷
关键词：
Wnt signaling; c-Myc; Miz-1; DNA methylation;
D O I：
暂无
中图分类号：
学科分类号：
摘要：
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 209myc. 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.
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页码：5923 / 5934
页数：11
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