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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Neoplasms / genetics*
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Bone Neoplasms / pathology
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Co-Repressor Proteins / genetics
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Co-Repressor Proteins / metabolism
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Gene Expression Regulation, Neoplastic*
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Genes, Tumor Suppressor
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Histone Deacetylases / metabolism
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Humans
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism
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Mice, Nude
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Protein Structure, Tertiary
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Protein-Lysine 6-Oxidase / genetics
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Protein-Lysine 6-Oxidase / metabolism
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Proto-Oncogene Protein c-fli-1 / genetics*
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Proto-Oncogene Protein c-fli-1 / metabolism
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RNA-Binding Protein EWS / genetics*
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RNA-Binding Protein EWS / metabolism
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Sarcoma, Ewing / genetics*
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Sarcoma, Ewing / pathology
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Transcription, Genetic
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Xenograft Model Antitumor Assays
Substances
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Co-Repressor Proteins
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EWS-FLI fusion protein
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Oncogene Proteins, Fusion
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Proto-Oncogene Protein c-fli-1
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RNA-Binding Protein EWS
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Histone Demethylases
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Protein-Lysine 6-Oxidase
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KDM1A protein, human
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Histone Deacetylases
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Mi-2 Nucleosome Remodeling and Deacetylase Complex