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Nat Med. 2014 Jul;20(7):732-40. doi: 10.1038/nm.3613. Epub 2014 Jun 29.

Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition.

Author information

1
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.
2
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
3
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
4
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
5
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.
6
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.
7
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
9
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.
10
Sanford-Burnham Medical Research, La Jolla, California, USA.
11
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.

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.

PMID:
24973920
PMCID:
PMC4108909
DOI:
10.1038/nm.3613
[Indexed for MEDLINE]
Free PMC Article
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