title: Activation of SOX2 expression by BRD4-NUT oncogenic fusion drives neoplastic transformation in NUT midline carcinoma.
abstract: BRD4 is implicated in the pathogenesis of a number of different cancers. It is also the target of translocation t(15;19) that accounts for the highly aggressive NUT midline carcinoma (NMC). We discovered that t(15;19) NMC cells display the ability to grow into stem cell-like spheres and express an exceptionally high level of the stem cell marker, SOX2. The BRD4-NUT fusion oncogene resulting from t(15;19) translocation is required for the abnormal activation of SOX2, which drives the stem cell-like proliferation and cellular transformation in NMC cells. SOX2 knockdown phenocopies the effects of BRD4-NUT inhibition, whereas ectopic SOX2 expression rescues the phenotype. The BRD4-NUT-induced abnormal SOX2 activation was observed in multiple NMC cell lines as well as in NMC primary tumors. We further demonstrate that BRD4-NUT oncoprotein recruits p300 to stimulate transcription activation and that inhibition of p300 represses SOX2 transcription in NMC cells. These studies identify this stem cell marker as a novel BRD4-NUT target that supports the highly aggressive transforming activity of t(15;19) carcinomas. Our study provides new mechanistic insights for understanding how alteration of BRD4 function by BRD4-NUT oncogene leads to the highly malignant NMC carcinoma. Because abnormal stem cell self-renewal is frequently observed during tumor formation and metastasis, the aberrant stem cell-like proliferation associated with BRD4 dysregulation observed in NMC carcinoma may have implications for studying the oncogenic mechanism of other BRD4-associated tumors.
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Ranran
authors.initials: R
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Helfer
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Hornick
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Janicki
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: French
authors.affiliation: Authors' Affiliations: Department of Microbiology, University of Pennsylvania Perelman School of Medicine; and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania; Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 510D; and Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts jianyou@mail.med.upenn.edu.
authors.forename: Jianxin
authors.initials: J
authors.lastname: You
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D011485:Protein Binding; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014230:Triazoles / Q000494:pharmacology; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; C471990:BRD4-NUT fusion oncogene protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D014230:Triazoles; D050880:p300-CBP Transcription Factors
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