title: The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers.
abstract: Epigenetic enzymes modulate signal transduction pathways in different biological contexts. We reasoned that epigenetic regulators might modulate the Hedgehog (HH) signaling pathway, a main driver of cell proliferation in various cancers including medulloblastoma. To test this hypothesis, we performed an unbiased small-molecule screen utilizing an HH-dependent reporter cell line (Light2 cells). We incubated Light2 cells with small molecules targeting different epigenetic modulators and identified four histone deacetylase inhibitors and a bromodomain and extra terminal domain (BET) protein inhibitor (I-BET151) that attenuate HH activity. I-BET151 was also able to inhibit the expression of HH target genes in Sufu(-/-) mouse embryonic fibroblasts, in which constitutive Gli activity is activated in a Smoothened (Smo)-independent fashion, consistent with it acting downstream of Smo. Knockdown of Brd4 (which encodes one of the BET proteins) phenocopies I-BET151 treatment, suggesting that Brd4 is a regulator of the HH signaling pathway. Consistent with this suggestion, Brd4 associates with the proximal promoter region of the Gli1 locus, and does so in a manner that can be reversed by I-BET151. Importantly, I-BET151 also suppressed the HH activity-dependent growth of medulloblastoma cells, in vitro and in vivo. These studies suggest that BET protein modulation may be an attractive therapeutic strategy for attenuating the growth of HH-dependent cancers, such as medulloblastoma.
authors.affiliation: From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and.
authors.forename: Jun
authors.initials: J
authors.lastname: Long
authors.affiliation: From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and.
authors.forename: Jezabel
authors.initials: J
authors.lastname: Rodriguez-Blanco
authors.affiliation: the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 33136 and.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastori
authors.affiliation: the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 33136 and.
authors.forename: Claude-Henry
authors.initials: CH
authors.lastname: Volmar
authors.affiliation: the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 33136 and the Sylvester Cancer Center and.
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.affiliation: From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and the Sylvester Cancer Center and Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida 33136.
authors.forename: Anthony
authors.initials: A
authors.lastname: Capobianco
authors.affiliation: From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and.
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.affiliation: From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and the Sylvester Cancer Center and.
authors.forename: Xin-Hai
authors.initials: XH
authors.lastname: Pei
authors.affiliation: the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 33136 and the Sylvester Cancer Center and nayad@med.miami.edu.
authors.forename: Nagi G
authors.initials: NG
authors.lastname: Ayad
authors.affiliation: From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and the Sylvester Cancer Center and Department of Biochemistry and Molecular Biology, University of Miami, Miami, Florida 33136 drobbins@med.miami.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018345:Mice, Knockout; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D000092468:Bromodomain Containing Proteins
chemical_list: D053823:Hedgehog Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A; C498520:Gli1 protein, mouse; C491022:Smo protein, mouse; C490763:Sufu protein, mouse
keywords: Bromodomain-containing Protein 4 (BRD4); Drug Screening; Epigenetics; Gli; Hedgehog Signaling Pathway; I-BET151; Medulloblastoma