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Oncogene. 2013 Oct 17;32(42):5089-100. doi: 10.1038/onc.2012.525. Epub 2012 Nov 26.

Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma.

Author information

1
Department of Oncological Sciences, Huntsman Cancer Institute, School of Medicine, Salt Lake City, UT, USA.

Abstract

Ewing sarcoma provides an important model for transcription-factor-mediated oncogenic transformation because of its reliance on the ETS-type fusion oncoprotein EWS/FLI. EWS/FLI functions as a transcriptional activator and transcriptional activation is required for its oncogenic activity. Here, we demonstrate that a previously less-well characterized transcriptional repressive function of the EWS/FLI fusion is also required for the transformed phenotype of Ewing sarcoma. Through comparison of EWS/FLI transcriptional profiling and genome-wide localization data, we define the complement of EWS/FLI direct downregulated target genes. We demonstrate that LOX is a previously undescribed EWS/FLI-repressed target that inhibits the transformed phenotype of Ewing sarcoma cells. Mechanistic studies demonstrate that the NuRD co-repressor complex interacts with EWS/FLI, and that its associated histone deacetylase and LSD1 activities contribute to the repressive function. Taken together, these data reveal a previously unknown molecular function for EWS/FLI, demonstrate a more highly coordinated oncogenic transcriptional hierarchy mediated by EWS/FLI than previously suspected, and implicate a new paradigm for therapeutic intervention aimed at controlling NuRD activity in Ewing sarcoma tumors.

PMID:
23178492
PMCID:
PMC3899696
DOI:
10.1038/onc.2012.525
[Indexed for MEDLINE]
Free PMC Article

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