Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition
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Author
Tang, Yujie
Gholamin, Sharareh
Schubert, Simone
Willardson, Minde I.
Lee, Alex
Bandopadhayay, Pratiti
Bergthold, Guillame
Masoud, Sabran
Nguyen, Brian
Vue, Nujsaubnusi
Balansay, Brianna
Yu, Furong
Oh, Sekyung
Woo, Pamelyn
Chen, Spenser
Ponnuswami, Anitha
Monje, Michelle
Atwood, Scott X.
Whitson, Ramon J.
Mitra, Siddhartha
Cheshier, Samuel H.
Qi, Jun
Beroukhim, Rameen
Tang, Jean Y.
Wechsler-Reya, Rob
Oro, Anthony E.
Link, Brian A.
Cho, Yoon-Jae
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/nm.3613Metadata
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Tang, Y., S. Gholamin, S. Schubert, M. I. Willardson, A. Lee, P. Bandopadhayay, G. Bergthold, et al. 2014. “Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition.” Nature medicine 20 (7): 732-740. doi:10.1038/nm.3613. http://dx.doi.org/10.1038/nm.3613.Abstract
Hedgehog signaling drives oncogenesis in several cancers and strategies targeting this pathway have been developed, most notably through inhibition of Smoothened. However, resistance to Smoothened inhibitors occurs via genetic changes of Smoothened or other downstream Hedgehog components. Here, we overcome these resistance mechanisms by modulating GLI transcription via inhibition of BET bromodomain proteins. We show the BET bromodomain protein, BRD4, regulates GLI transcription downstream of SMO and SUFU and chromatin immunoprecipitation studies reveal BRD4 directly occupies GLI1 and GLI2 promoters, with a substantial decrease in engagement of these sites upon 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-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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108909/pdf/Terms of Use
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:13890716
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