Your browser doesn't support javascript.
loading
GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer.
Bevill, Samantha M; Olivares-Quintero, Jose F; Sciaky, Noah; Golitz, Brian T; Singh, Darshan; Beltran, Adriana S; Rashid, Naim U; Stuhlmiller, Timothy J; Hale, Andrew; Moorman, Nathaniel J; Santos, Charlene M; Angus, Steven P; Zawistowski, Jon S; Johnson, Gary L.
Afiliação
  • Bevill SM; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Olivares-Quintero JF; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Sciaky N; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Golitz BT; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Singh D; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Beltran AS; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Rashid NU; Department of Biostatistics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Stuhlmiller TJ; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Hale A; Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Moorman NJ; Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Santos CM; Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Angus SP; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Zawistowski JS; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
  • Johnson GL; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. glj@med.unc.edu.
Mol Cancer Res ; 17(7): 1503-1518, 2019 07.
Article em En | MEDLINE | ID: mdl-31000582
Screening of an inhibitor library targeting kinases and epigenetic regulators identified several molecules having antiproliferative synergy with extraterminal domain (BET) bromodomain (BD) inhibitors (JQ1, OTX015) in triple-negative breast cancer (TNBC). GSK2801, an inhibitor of BAZ2A/B BDs, of the imitation switch chromatin remodeling complexes, and BRD9, of the SWI/SNF complex, demonstrated synergy independent of BRD4 control of P-TEFb-mediated pause-release of RNA polymerase II. GSK2801 or RNAi knockdown of BAZ2A/B with JQ1 selectively displaced BRD2 at promoters/enhancers of ETS-regulated genes. Additional displacement of BRD2 from rDNA in the nucleolus coincided with decreased 45S rRNA, revealing a function of BRD2 in regulating RNA polymerase I transcription. In 2D cultures, enhanced displacement of BRD2 from chromatin by combination drug treatment induced senescence. In spheroid cultures, combination treatment induced cleaved caspase-3 and cleaved PARP characteristic of apoptosis in tumor cells. Thus, GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces apoptosis of TNBC. IMPLICATIONS: Synergistic inhibition of BDs encoded in BAZ2A/B, BRD9, and BET proteins induces apoptosis of TNBC by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Cromossômicas não Histona / Receptores de Superfície Celular / Neoplasias de Mama Triplo Negativas / Proteínas do Tecido Nervoso Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Revista: Mol Cancer Res Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Fatores de Transcrição / Proteínas Cromossômicas não Histona / Receptores de Superfície Celular / Neoplasias de Mama Triplo Negativas / Proteínas do Tecido Nervoso Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Revista: Mol Cancer Res Assunto da revista: BIOLOGIA MOLECULAR / NEOPLASIAS Ano de publicação: 2019 Tipo de documento: Article