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J Biol Chem. 2014 Dec 19;289(51):35494-502. doi: 10.1074/jbc.M114.595348. Epub 2014 Oct 29.

The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers.

Author information

1
From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and.
2
the Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 33136 and.
3
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.
4
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.
5
From the Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery and the Sylvester Cancer Center and.
6
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.
7
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.

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.

KEYWORDS:

Bromodomain-containing Protein 4 (BRD4); Drug Screening; Epigenetics; Gli; Hedgehog Signaling Pathway; I-BET151; Medulloblastoma

PMID:
25355313
PMCID:
PMC4271234
DOI:
10.1074/jbc.M114.595348
[Indexed for MEDLINE]
Free PMC Article

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