title: Transformation resistance in a premature aging disorder identifies a tumor-protective function of BRD4.
abstract: Advanced age and DNA damage accumulation are prominent risk factors for cancer. The premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS) provides a unique opportunity for studying the interplay between DNA damage and aging-associated tumor mechanisms, given that HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neoplastic transformation. Resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells, leading to inhibition of oncogenic dedifferentiation. BRD4 also inhibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals. BRD4-mediated tumor protection is clinically relevant given that a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific roles for BRD4 in tumorigenesis.
authors.affiliation: National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernandez
authors.affiliation: National Cancer Institute, NIH, Bethesda, MD 20892, USA; Cancer Epigenetics Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, UK; UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Scaffidi
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert-Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
authors.forename: Elke
authors.initials: E
authors.lastname: Markert
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Sushil
authors.initials: S
authors.lastname: Rane
authors.affiliation: National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
mesh_terms: D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011371:Progeria / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins