title: Inhibition of BET bromodomain targets genetically diverse glioblastoma.
abstract: OBJECTIVE
  Glioblastoma is refractory to conventional therapies. The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that selectively bind to acetylated lysine residues on histone tails. These proteins recently emerged as important therapeutic targets in NUT midline carcinoma and several types of hematopoietic cancers. In this study, the therapeutic potential of a novel BET bromodomain inhibitor, JQ1, was assessed in a panel of genetically heterogeneous glioblastoma samples.
  
  
  METHODS
  The antineoplastic effects of JQ1 were shown using ex vivo cultures derived from primary glioblastoma xenograft lines and surgical specimens of different genetic background. The in vivo efficacy was assessed in orthotopic glioblastoma tumors.
  
  
  RESULTS
  We showed that JQ1 induced marked G1 cell-cycle arrest and apoptosis, which was phenocopied by knockdown of individual BET family members. JQ1 treatment resulted in significant changes in expression of genes that play important roles in glioblastoma such as c-Myc, p21(CIP1/WAF1), hTERT, Bcl-2, and Bcl-xL. Unlike the observations in some hematopoietic cancer cell lines, exogenous c-Myc did not significantly protect glioblastoma cells against JQ1. In contrast, ectopically expressed Bcl-xL partially rescued cells from JQ1-induced apoptosis, and knockdown of p21(CIP1/WAF1) attenuated JQ1-induced cell-cycle arrest. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these frequently mutated signaling pathways may not confer resistance to JQ1. Furthermore, JQ1 significantly repressed growth of orthotopic glioblastoma tumors.
  
  
  CONCLUSIONS
  Our results suggest potentially broad therapeutic use of BET bromodomain inhibitors for treating genetically diverse glioblastoma tumors.
authors: Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors: Zhixiang
authors: Z
authors: Cheng
authors: Yuanying
authors: Y
authors: Gong
authors: Yufang
authors: Y
authors: Ma
authors: Kaihua
authors: K
authors: Lu
authors: Xiang
authors: X
authors: Lu
authors: Larry A
authors: LA
authors: Pierce
authors: Reid C
authors: RC
authors: Thompson
authors: Susanne
authors: S
authors: Muller
authors: Stefan
authors: S
authors: Knapp
authors: Jialiang
authors: J
authors: Wang
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; D017346:Protein Serine-Threonine Kinases
references: Nature. 2011 Oct 02;478(7370):529-33
references: 21964340
references: Cold Spring Harb Symp Quant Biol. 2008;73:427-37
references: 19150964
references: Nature. 2011 Aug 03;478(7370):524-8
references: 21814200
references: Curr Protoc Pharmacol. 2011 Mar;Chapter 14:Unit 14.16
references: 21743824
references: Nature. 2008 Oct 23;455(7216):1061-8
references: 18772890
references: Blood. 2012 Oct 4;120(14):2843-52
references: 22904298
references: Aging Cell. 2011 Apr;10(2):349-61
references: 21342417
references: Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19408-13
references: 23129625
references: Acta Neuropathol. 2008 Jul;116(1):87-95
references: 18369647
references: Oncogene. 2008 Apr 3;27(15):2237-42
references: 17934517
references: Nature. 2006 Dec 7;444(7120):756-60
references: 17051156
references: Nat Rev Cancer. 2012 Jun 22;12(7):465-77
references: 22722403
references: Nature. 2012 Aug 23;488(7412):522-6
references: 22854781
references: Cancer Cell. 2011 Dec 13;20(6):810-7
references: 22137795
references: Cell. 2011 Sep 16;146(6):904-17
references: 21889194
references: Mol Cell. 2005 Aug 19;19(4):535-45
references: 16109377
references: Stem Cells. 2010 Jan;28(1):17-28
references: 19921751
references: Cell. 2012 Jul 6;150(1):12-27
references: 22770212
references: Cancer Res. 2011 Jun 15;71(12):4055-60
references: 21628493
references: Cancer Cell. 2006 May;9(5):391-403
references: 16697959
references: Mol Cell Biol. 2002 Jun;22(11):3794-802
references: 11997514
references: Cancer Cell. 2010 Jan 19;17(1):98-110
references: 20129251
references: Neuro Oncol. 2012 Jul;14(7):870-81
references: 22711607
references: J Cell Physiol. 2011 Nov;226(11):2762-81
references: 21302297
references: Nat Rev Genet. 2007 Apr;8(4):263-71
references: 17363975
references: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3041-6
references: 22323597
references: Nature. 2004 Nov 18;432(7015):396-401
references: 15549107
references: N Engl J Med. 2012 Aug 16;367(7):647-57
references: 22894577
references: PLoS One. 2008;3(11):e3769
references: 19020659
references: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74
references: 21949397
references: Dev Dyn. 2009 Apr;238(4):908-17
references: 19301389
references: J Med Chem. 2011 Jun 9;54(11):3827-38
references: 21568322
references: Nat Med. 2011 Mar;17(3):330-9
references: 21386836
references: Mol Cancer Ther. 2002 Jul;1(9):707-17
references: 12479367
references: Mol Cell. 2005 Aug 19;19(4):523-34
references: 16109376
references: Proc Natl Acad Sci U S A. 2012 May 1;109(18):6927-32
references: 22509028
references: Nature. 2010 Dec 23;468(7327):1067-73
references: 20871596
references: Ann N Y Acad Sci. 2008 Oct;1142:108-32
references: 18990124
references: Cell. 2012 Mar 30;149(1):22-35
references: 22464321
references: Nature. 2010 Dec 23;468(7327):1119-23
references: 21068722
references: Cancer Cell. 2012 Mar 20;21(3):283-96
references: 22439924
references: Cell. 2012 Aug 17;150(4):673-84
references: 22901802
references: Clin Cancer Res. 2011 Jan 1;17(1):111-21
references: 21208905
references: Cancer Res. 2010 Apr 15;70(8):3228-38
references: 20354191
references: N Engl J Med. 2008 Jul 31;359(5):492-507
references: 18669428
references: Cancer Res. 2012 Nov 15;72(22):6065-75
references: 22986743
references: Expert Rev Mol Med. 2011 Sep 13;13:e29
references: 21933453
references: Mol Cancer Ther. 2007 Mar;6(3):1167-74
references: 17363510
references: Cell. 2008 Jul 11;134(1):62-73
references: 18614011