EWS/ETS regulates the expression of the dickkopf family in ewing family tumor cells

Yoshitaka Miyagawa, Hajime Okita, Mitsuko Itagaki, Masashi Toyoda, Yohko U. Katagiri, Junichiro Fujimoto, Jun Ichi Hata, Akihiro Umezawa, Nobutaka Kiyokawa

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Abstract

Background: The Dickkopf (DKK) family comprises a set of proteins that function as regulators of Wnt/b-catenin signaling and has a crucial role in development. Recent studies have revealed the involvement of this family in tumorigenesis, however their role in tumorigenesis is still remained unclear. Methodology/Principal Findings: We found increased expression of DKK2 but decreased expression of DKK1 in Ewing family tumor (EFT) cells. We showed that EFT-specific EWS/ETS fusion proteins enhance the DKK2 promoter activity, but not DKK1 promoter activity, via ets binding sites (EBSs) in the 59 upstream region. EWS/ETS-mediated transactivation of the promoter was suppressed by the deletion and mutation of EBSs located upstream of the DKK2 gene. Interestingly, the inducible expression of EWS/ETS resulted in the strong induction of DKK2 expression and inhibition of DKK1 expression in human primary mesenchymal progenitor cells that are thought to be a candidate of cell origin of EFT. In addition, using an EFT cell line SK-ES1 cells, we also demonstrated that the expression of DKK1 and DKK2 is mutually exclusive, and the ectopic expression of DKK1, but not DKK2, resulted in the suppression of tumor growth in immuno-deficient mice. Conclusions/Significance: Our results suggested that DKK2 could not functionally substitute for DKK1 tumor-suppressive effect in EFT. Given the mutually exclusive expression of DKK1 and DKK2, EWS/ETS regulates the transcription of the DKK family, and the EWS/ETS-mediated DKK2 up-regulation could affect the tumorigenicity of EFT in an indirect manner.

Original languageEnglish
Article numbere4634
JournalPloS one
Volume4
Issue number2
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Miyagawa, Y., Okita, H., Itagaki, M., Toyoda, M., Katagiri, Y. U., Fujimoto, J., Hata, J. I., Umezawa, A., & Kiyokawa, N. (2009). EWS/ETS regulates the expression of the dickkopf family in ewing family tumor cells. PloS one, 4(2), [e4634]. https://doi.org/10.1371/journal.pone.0004634