EWS/ETS regulates the expression of the Dickkopf family in Ewing family tumor cells.
BACKGROUND
The Dickkopf (DKK) family comprises a set of proteins that function as regulators of Wnt/beta-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.


RESULTS
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 5' 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
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.
Miyagawa
Yoshitaka
Y
Department of Developmental Biology, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
Okita
Hajime
H
Itagaki
Mitsuko
M
Toyoda
Masashi
M
Katagiri
Yohko U
YU
Fujimoto
Junichiro
J
Hata
Jun-ichi
J
Umezawa
Akihiro
A
Kiyokawa
Nobutaka
N
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1 / Q000502:physiology*; D034802:RNA-Binding Protein EWS / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C501126:DKK1 protein, human; C498622:DKK2 protein, human; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D050784:Proto-Oncogene Protein c-ets-1; D034802:RNA-Binding Protein EWS