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EWS/FLI and Its Downstream Target NR0B1 Interact Directly to Modulate Transcription and Oncogenesis in Ewing's Sarcoma

¹ Department of Oncological Sciences, University of Utah School of Medicine; ² Center for Children's Cancer Research, Huntsman Cancer Institute and ³ Division of Pediatric Hematology/Oncology, University of Utah, Salt Lake City, Utah; Departments of ⁴ Human Genetics and ⁵ Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California

Requests for reprints: Stephen L. Lessnick, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112. Phone: 801-585-9268; Fax: 801-585-5357; E-mail: stephen.lessnick{at}hci.utah.edu.

Most Ewing's sarcomas harbor chromosomal translocations that encode fusions between EWS and ETS family members. The most common fusion, EWS/FLI, consists of an EWSR1-derived strong transcriptional activation domain fused, in-frame, to the DNA-binding domain–containing portion of FLI1. EWS/FLI functions as an aberrant transcription factor to regulate genes that mediate the oncogenic phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a corepressor protein, and likely plays a transcriptional role in tumorigenesis. However, the genes that NR0B1 regulates and the transcription factors it interacts with in Ewing's sarcoma are largely unknown. We used transcriptional profiling and chromatin immunoprecipitation to identify genes that are regulated by NR0B1, and compared these data to similar data for EWS/FLI. Although the transcriptional profile overlapped as expected, we also found that the genome-wide localization of NR0B1 and EWS/FLI overlapped as well, suggesting that they regulate some genes coordinately. Further analysis revealed that NR0B1 and EWS/FLI physically interact. This protein-protein interaction is likely to be relevant for the development of Ewing's sarcoma because mutations in NR0B1 that disrupt the interaction have transcriptional consequences and also abrogate oncogenic transformation. Taken together, these data suggest that EWS/FLI and NR0B1 physically interact, coordinately modulate gene expression, and mediate the transformed phenotype of Ewing's sarcoma. [Cancer Res 2009;69(23):9047–55]

Key Words: EWS/FLI • NR0B1 • DAX1 • Ewing's sarcoma

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				K. Gangwal, D. Close, C. A. Enriquez, C. P. Hill, and S. L. Lessnick Emergent Properties of EWS/FLI Regulation via GGAA Microsatellites in Ewing's Sarcoma Genes & Cancer, February 1, 2010; 1(2): 177 - 187. [Abstract] [Full Text] [PDF]