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

J. D.F. Licchesi, L. Van Neste, V. K. Tiwari, L. Cope, X. Lin, S. B. Baylin, J. G. Herman

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5923-5934
Number of pages12
JournalOncogene
Volume29
Issue number44
DOIs
StatePublished - Nov 4 2010

Keywords

  • DNA methylation
  • Miz-1
  • WIF-1
  • Wnt signaling
  • c-Myc

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Licchesi, J. D. F., Van Neste, L., Tiwari, V. K., Cope, L., Lin, X., Baylin, S. B., & Herman, J. G. (2010). Transcriptional regulation of Wnt inhibitory factor-1 by Miz-1/c-Myc. Oncogene, 29(44), 5923-5934. https://doi.org/10.1038/onc.2010.322