title: Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma.
abstract: Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo.
authors.affiliation: Department of Pediatrics, Children's Hospital Colorado and University of Colorado, Denver, CO, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Venkataraman
authors.forename: Irina
authors.initials: I
authors.lastname: Alimova
authors.forename: Ilango
authors.initials: I
authors.lastname: Balakrishnan
authors.forename: Peter
authors.initials: P
authors.lastname: Harris
authors.forename: Diane K
authors.initials: DK
authors.lastname: Birks
authors.forename: Andrea
authors.initials: A
authors.lastname: Griesinger
authors.forename: Vladimir
authors.initials: V
authors.lastname: Amani
authors.forename: Brian
authors.initials: B
authors.lastname: Cristiano
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Michael
authors.initials: M
authors.lastname: Handler
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Rajeev
authors.initials: R
authors.lastname: Vibhakar
mesh_terms: D000818:Animals; D017209:Apoptosis; D001381:Azepines / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D002648:Child; D020869:Gene Expression Profiling; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins