TY - JOUR
T1 - EWS/ETS regulates the expression of the dickkopf family in ewing family tumor cells
AU - Miyagawa, Yoshitaka
AU - Okita, Hajime
AU - Itagaki, Mitsuko
AU - Toyoda, Masashi
AU - Katagiri, Yohko U.
AU - Fujimoto, Junichiro
AU - Hata, Jun Ichi
AU - Umezawa, Akihiro
AU - Kiyokawa, Nobutaka
N1 - Funding Information:
Funding: This work was supported in part by Health and Labour Sciences Research Grants (the 3rd term comprehensive 10-year-strategy for cancer control H19-010, Research on Children and Families H18-005 and H19-003, Research on Human Genome Tailor made and Research on Publicly Essential Drugs and Medical Devices H18-005) and Grant for Child Health and Development from the Ministry of Health, Labour and Welfare of Japan, JSPS. KAKENHI 18790263. This work was also supported by CREST, JST, a grant from the Japan Health Sciences Foundation for Research on Publicly Essential Drugs and Medical Devices and the Budget for Nuclear Research of the Ministry of Education, Culture, Sports, Science and Technology, based on the screening and counseling by the Atomic Energy Commission. Y. Miyagawa is an Awardee of a Research Resident Fellowship from the Foundation for Promotion of Cancer Research (Japan) for the 3rd Term Comprehensive 10-Year-Strategy for Cancer Control. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2009 Miyagawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0004634
DO - 10.1371/journal.pone.0004634
M3 - Article
AN - SCOPUS:84864277344
SN - 1932-6203
VL - 4
JO - PLoS One
JF - PLoS One
IS - 2
M1 - e4634
ER -