title: Mechanism and relevance of EWS/FLI-mediated transcriptional repression in Ewing sarcoma.
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.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, School of Medicine, Salt Lake City, UT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sankar
authors.forename: R
authors.initials: R
authors.lastname: Bell
authors.forename: B
authors.initials: B
authors.lastname: Stephens
authors.forename: R
authors.initials: R
authors.lastname: Zhuo
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.forename: D J
authors.initials: DJ
authors.lastname: Bearss
authors.forename: S L
authors.initials: SL
authors.lastname: Lessnick
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006655:Histone Deacetylases / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000235:genetics* / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D056970:Co-Repressor Proteins; C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D056466:Histone Demethylases; D008249:Protein-Lysine 6-Oxidase; C495195:KDM1A protein, human; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex