title: BCL11B is up-regulated by EWS/FLI and contributes to the transformed phenotype in Ewing sarcoma.
abstract: The EWS/FLI translocation product is the causative oncogene in Ewing sarcoma and acts as an aberrant transcription factor. EWS/FLI dysregulates gene expression during tumorigenesis by abnormally activating or repressing genes. The expression levels of thousands of genes are affected in Ewing sarcoma, however, it is unknown which of these genes contribute to the transformed phenotype. Here we characterize BCL11B as an up-regulated EWS/FLI target that is necessary for the maintenance of transformation in patient derived Ewing sarcoma cells lines. BCL11B, a zinc finger transcription factor, acts as a transcriptional repressor in Ewing's sarcoma and contributes to the EWS/FLI repressed gene signature. BCL11B repressive activity is mediated by the NuRD co-repressor complex. We further demonstrate that re-expression of SPRY1, a repressed target of BCL11B, limits the transformation capacity of Ewing sarcoma cells. These data define a new pathway downstream of EWS/FLI required for oncogenic maintenance in Ewing sarcoma.
authors.affiliation: Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, United States of America.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Wiles
authors.forename: Bianca
authors.initials: B
authors.lastname: Lui-Sargent
authors.forename: Russell
authors.initials: R
authors.lastname: Bell
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lessnick
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology*; D034802:RNA-Binding Protein EWS / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000378:metabolism / Q000503:physiopathology*; D016415:Sequence Alignment; D017423:Sequence Analysis, RNA; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C479740:BCL11B protein, human; C106031:EWS-FLI fusion protein; D008565:Membrane Proteins; D009841:Oligonucleotides; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D012097:Repressor Proteins; C486055:SPRY1 protein, human; D025521:Tumor Suppressor Proteins; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex