title: The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects.
abstract: Patients with neuroblastoma associated with MYCN oncogene amplification experience a very poor prognosis. BET bromodomain inhibitors are among the most promising novel anticancer agents as they block BRD3 and BRD4 from activating oncogene transcription. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission in many murine models.
  
  
  
  MYCN-amplified neuroblastoma cells were treated with vehicle control, the BET bromodomain inhibitor JQ1, the histone deacetylase inhibitor panobinostat, or the combination of JQ1 and panobinostat. Genes modulated by JQ1, panobinostat, or the combination therapy were identified by Affymetrix microarray, and cell proliferation and apoptosis were examined by Alamar blue assays and flow cytometry analysis. Modulation of LIN28B promoter activity by BRD3 and BRD4 was examined by chromatin immunoprecipitation and luciferase assays. In addition, neuroblastoma-bearing mice were treated with vehicle control, JQ1, and/or panobinostat.
  
  
  
  LIN28B was one of the top genes synergistically reduced by JQ1 and panobinostat. BRD3 and BRD4 directly bound to the LIN28B gene promoter and activated LIN28B gene transcription, and knocking down LIN28B reduced the expression of N-Myc protein, but not N-Myc mRNA. JQ1 and panobinostat synergistically reduced LIN28B gene and N-Myc protein expression, and synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal nonmalignant cells in vitro In neuroblastoma-bearing mice, JQ1 and panobinostat synergistically and considerably reduced N-Myc protein expression in tumor tissues and blocked tumor progression.
  
  
  
  Our findings have identified a novel strategy to reduce the N-Myc oncoprotein expression and a novel therapeutic approach for the treatment of aggressive neuroblastoma. Clin Cancer Res; 22(10); 2534-44. ©2016 AACR.
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, New South Wales, Australia. School of Biotechnology and Biomolecular Sciences, University of New South Wales Faculty of Science, University of New South Wales Australia, Sydney, New South Wales, Australia.
authors.forename: Jeyran
authors.initials: J
authors.lastname: Shahbazi
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, New South Wales, Australia.
authors.forename: Pei Y
authors.initials: PY
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, New South Wales, Australia.
authors.forename: Bernard
authors.initials: B
authors.lastname: Atmadibrata
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, New South Wales, Australia. Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, New South Wales, Australia. School of Women's & Children's Health, University of New South Wales Australia, Randwick, New South Wales, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales Australia, Randwick, New South Wales, Australia. School of Women's & Children's Health, University of New South Wales Australia, Randwick, New South Wales, Australia. tliu@ccia.unsw.edu.au.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D000077767:Panobinostat; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000077767:Panobinostat; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; C561695:(+)-JQ1 compound; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins