title: The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation.
abstract: Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I-BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases.
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136;
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastori
authors.affiliation: Institute of Genomics, School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China; St. Laurent Institute, Woburn, MA 01801;
authors.forename: Philipp
authors.initials: P
authors.lastname: Kapranov
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136;
authors.forename: Clara
authors.initials: C
authors.lastname: Penas
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136;
authors.forename: Veronica
authors.initials: V
authors.lastname: Peschansky
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136;
authors.forename: Claude-Henry
authors.initials: CH
authors.lastname: Volmar
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905;
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.affiliation: Department of Neurosurgery, University of Miami, Miami, FL 33136.
authors.forename: Amade
authors.initials: A
authors.lastname: Bregy
authors.affiliation: Department of Neurosurgery, University of Miami, Miami, FL 33136.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Komotar
authors.affiliation: St. Laurent Institute, Woburn, MA 01801;
authors.forename: Georges
authors.initials: G
authors.lastname: St Laurent
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136; cwahlestedt@med.miami.edu NAyad@med.miami.edu.
authors.forename: Nagi G
authors.initials: NG
authors.lastname: Ayad
authors.affiliation: Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL 33136; cwahlestedt@med.miami.edu NAyad@med.miami.edu.
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A; C561566:HOTAIR long untranslated RNA, human
keywords: BRD4; I-BET151; epigenetics; glioblastoma; long noncoding RNAs