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

Jun Long, Bin Li, Jezabel Rodriguez-Blanco, Chiara Pastori, Claude Henry Volmar, Claes R Wahlestedt, Anthony J Capobianco, Feng Bai, Xin-Hai Pei, Nagi Ayad, David J Robbins

Research output: Contribution to journalArticle

56 Citations (Scopus)

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 theHHactivity-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.

Original languageEnglish
Article numberA32
Pages (from-to)35494-35502
Number of pages9
JournalJournal of Biological Chemistry
Volume289
Issue number51
DOIs
StatePublished - Dec 19 2014

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Hedgehog Proteins
Hedgehogs
Medulloblastoma
Growth
Epigenomics
Neoplasms
Proteins
Signal transduction
Molecules
Histone Deacetylase Inhibitors
Cell proliferation
Fibroblasts
Genetic Promoter Regions
Modulators
Genes
Cells
Modulation
GSK1210151A
Smoothened Receptor
Signal Transduction

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers. / Long, Jun; Li, Bin; Rodriguez-Blanco, Jezabel; Pastori, Chiara; Volmar, Claude Henry; Wahlestedt, Claes R; Capobianco, Anthony J; Bai, Feng; Pei, Xin-Hai; Ayad, Nagi; Robbins, David J.

In: Journal of Biological Chemistry, Vol. 289, No. 51, A32, 19.12.2014, p. 35494-35502.

Research output: Contribution to journalArticle

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