Abstract
The chromosomal translocation t(2;13), characteristic for the aggressive childhood cancer alveolar rhabdomyosarcoma (aRMS), generates the chimeric transcription factor PAX3/FKHR with a well known oncogenic role. However, the molecular mechanisms mediating essential pathophysiological functions remain poorly defined. Here, we used comparative expression profiling of PAX3/FKHR silencing in vitro and PAX3/FKHR-specific gene signatures in vivo to identify physiologically important target genes. Hereby, 51 activated genes, both novel and known, were identified. We also found repression of skeletal muscle-specific genes suggesting that PAX3/FKHR blocks further differentiation of aRMS cells. Importantly, TFAP2B was validated as direct target gene mediating the anti-apoptotic function of PAX3/FKHR. Hence, we developed a pathophysiologically relevant transcriptional profile of PAX3/FKHR and identified a critical target gene for aRMS development.
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Acknowledgements
We thank FG Barr (University of Pennsylvania, Philadelphia, PA) and R Fässler (Max-Planck-Institute, Münich, Germany) for providing cDNA constructs, A Patrignani (FGCZ) for excellent technical assistance with Affymetrix experiments and M Dettling for performing principal component analysis. This work was supported by Swiss National Science Foundation, grant nos. 3100–067841 and 3100–109837 and the Schweizerische Forschungsstiftung Kind und Krebs.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Ebauer, M., Wachtel, M., Niggli, F. et al. Comparative expression profiling identifies an in vivo target gene signature with TFAP2B as a mediator of the survival function of PAX3/FKHR. Oncogene 26, 7267–7281 (2007). https://doi.org/10.1038/sj.onc.1210525
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DOI: https://doi.org/10.1038/sj.onc.1210525
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