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Abstract
Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00241-13.
ACKNOWLEDGMENTS
S.S. acknowledges support from the HHMI Med into Grad program at the University of Utah (U2M2G). This work was supported by NIH/NCI grants R01 CA140394 (to S.L.L.) and P30 CA042014 (to the Huntsman Cancer Institute).
We thank Alana Welm for discussions and critical reading of the manuscript and for generously providing us with immunodeficient mice, Michael Monument for providing the Ewing sarcoma patient tumor RNA, and Wen Luo and members of the Lessnick and Beckerle laboratories for helpful discussions and reagents.