Journal Article

The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor <i>DICKKOPF-1</i> gene and antagonizes β-catenin/TCF-mediated transcription

Diego Navarro, Noelia Agra, Ángel Pestaña, Javier Alonso and José M. González-Sancho

in Carcinogenesis

Volume 31, issue 3, pages 394-401
Published in print March 2010 | ISSN: 0143-3334
Published online December 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp317
The EWS/FLI1 oncogenic protein inhibits expression of the Wnt inhibitor DICKKOPF-1 gene and antagonizes β-catenin/TCF-mediated transcription

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Tumours of the Ewing family, which comprise Ewing's sarcoma and peripheral primitive neuroectodermal tumours, are highly aggressive and mostly affect children and adolescents. They are characterized by chromosomal translocations leading to the generation of fusion proteins between EWS (or very rarely FUS) and members of the E-twenty-six (ETS) family of transcription factors that are capable of transforming cells. EWS/FLI1, the most frequent fusion, is thought to cause transformation through activation or repression of specific target genes. We present evidence demonstrating that the Wnt inhibitor and β-catenin/T-cell factor (TCF)-responsive gene DICKKOPF-1 (DKK-1) is a transcriptional target of EWS/FLI1, which can inhibit both basal and β-catenin-induced transactivation of the DKK-1 promoter. Moreover, our data indicate that EWS/FLI1 has a more general effect on β-catenin/TCF-mediated transcription since it can block transactivation of a consensus β-catenin/TCF reporter construct. Consistently, Ewing tumour cells expressing different EWS/ETS translocations cannot engage β-catenin/TCF-dependent transcription, whereas silencing of EWS/FLI1 restores β-catenin responsiveness in A673 and RD-ES Ewing tumour cells. Accordingly, gene set enrichment analysis shows that β-catenin/TCF target genes are significantly enriched among genes downregulated by EWS/FLI1 in the Ewing cell line A673. Mechanistically, the inhibitory effect of EWS/FLI1 can be overcome by a constitutively active TCF4 protein (TCF4-VP16). Moreover, EWS/FLI1 binds lymphoid enhancer factor 1, a TCF family member, and interferes with its binding to β-catenin, which could explain its negative effect on β-catenin/TCF-mediated transcription. Our results show that EWS/FLI1 inhibits both DKK-1 expression as well as β-catenin/TCF-dependent transcription, which could contribute to progression of tumours of the Ewing family.

Journal Article.  6219 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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