title: Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition.
abstract: Hedgehog signaling drives oncogenesis in several cancers, and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened (SMO). However, resistance to Smoothened inhibitors occurs by genetic changes of Smoothened or other downstream Hedgehog components. Here we overcome these resistance mechanisms by modulating GLI transcription through inhibition of bromo and extra C-terminal (BET) bromodomain proteins. We show that BRD4 and other BET bromodomain proteins regulate GLI transcription downstream of SMO and suppressor of fused (SUFU), and chromatin immunoprecipitation studies reveal that BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites after treatment with JQ1, a small-molecule inhibitor targeting BRD4. Globally, genes associated with medulloblastoma-specific GLI1 binding sites are downregulated in response to JQ1 treatment, supporting direct regulation of GLI activity by BRD4. Notably, patient- and GEMM (genetically engineered mouse model)-derived Hedgehog-driven tumors (basal cell carcinoma, medulloblastoma and atypical teratoid rhabdoid tumor) respond to JQ1 even when harboring genetic lesions rendering them resistant to Smoothened antagonists. Altogether, our results reveal BET proteins as critical regulators of Hedgehog pathway transcriptional output and nominate BET bromodomain inhibitors as a strategy for treating Hedgehog-driven tumors with emerged or a priori resistance to Smoothened antagonists.
authors: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors: Yujie
authors: Y
authors: Tang
authors: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors: Sharareh
authors: S
authors: Gholamin
authors: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors: Simone
authors: S
authors: Schubert
authors: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Minde I
authors: MI
authors: Willardson
authors: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors: Alex
authors: A
authors: Lee
authors: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Pediatric Neuro-oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [4] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors: Pratiti
authors: P
authors: Bandopadhayay
authors: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Pediatric Neuro-oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors: Guillame
authors: G
authors: Bergthold
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Sabran
authors: S
authors: Masoud
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Brian
authors: B
authors: Nguyen
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Nujsaubnusi
authors: N
authors: Vue
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Brianna
authors: B
authors: Balansay
authors: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors: Furong
authors: F
authors: Yu
authors: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors: Sekyung
authors: S
authors: Oh
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Pamelyn
authors: P
authors: Woo
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Spenser
authors: S
authors: Chen
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Anitha
authors: A
authors: Ponnuswami
authors: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors: Michelle
authors: M
authors: Monje
authors: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors: Scott X
authors: SX
authors: Atwood
authors: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors: Ramon J
authors: RJ
authors: Whitson
authors: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors: Siddhartha
authors: S
authors: Mitra
authors: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors: Samuel H
authors: SH
authors: Cheshier
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Jun
authors: J
authors: Qi
authors: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Rameen
authors: R
authors: Beroukhim
authors: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors: Jean Y
authors: JY
authors: Tang
authors: Sanford-Burnham Medical Research, La Jolla, California, USA.
authors: Rob
authors: R
authors: Wechsler-Reya
authors: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors: Anthony E
authors: 000000026261138X
authors: AE
authors: Oro
authors: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Brian A
authors: BA
authors: Link
authors: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: James E
authors: JE
authors: Bradner
authors: 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA. [3] Stanford Cancer Institute, Stanford University Medical Center, Stanford, California, USA.
authors: Yoon-Jae
authors: YJ
authors: Cho
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D044127:Epigenesis, Genetic; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008024:Ligands; D051379:Mice; D009374:Neoplasms, Experimental / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014230:Triazoles / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse