The Hedgehog (Hh) pathway can drive oncogenesis, and current strategies to target it mainly focus on inhibitors of the G protein-coupled receptor Smoothened (SMO). SMO activates the downstream transcription factors GLI1 and GLI2, which transactivate Hh target genes. SMO inhibitors have demonstrated clinical efficacy, but resistance usually develops. Tang et al. now report that the epigenetic regulator BRD4, a BET bromodomain protein, controls GLI transcription by binding to the GLI1 and GLI2 promoters. The BRD4 inhibitor JQ1 was shown to downregulate Hh signalling, and had antitumour activity even in tumours that were resistant to SMO inhibitors.
Tang, Y. et al. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nature Med. 20, 732–740 (2014)
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Flemming, A. Epigenetic target in Hedgehog-driven tumours. Nat Rev Drug Discov 13, 654 (2014). https://doi.org/10.1038/nrd4428