@article{0c4c3072eeed41fd8880112ba3e2f0e3,
title = "Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition",
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.",
author = "Yujie Tang and Sharareh Gholamin and Simone Schubert and Willardson, {Minde I.} and Alex Lee and Pratiti Bandopadhayay and Guillame Bergthold and Sabran Masoud and Brian Nguyen and Nujsaubnusi Vue and Brianna Balansay and Furong Yu and Sekyung Oh and Pamelyn Woo and Spenser Chen and Anitha Ponnuswami and Michelle Monje and Atwood, {Scott X.} and Whitson, {Ramon J.} and Siddhartha Mitra and Cheshier, {Samuel H.} and Jun Qi and Rameen Beroukhim and Tang, {Jean Y.} and Rob Wechsler-Reya and Oro, {Anthony E.} and Link, {Brian A.} and Bradner, {James E.} and Cho, {Yoon Jae}",
note = "Funding Information: This work was supported the St. Baldrick{\textquoteright}s Foundation Scholar Award (Y.-J.C.), a Beirne Faculty Scholar Endowment (Y.-J.C.), US National Institutes of Health (NIH) grant U01-CA176287 (Y.-J.C.), an Alex{\textquoteright}s Lemonade Stand Foundation Young Investigator Award (Y.T.), the Damon-Runyon Cancer Research Foundation (J.Q. and J.E.B.), NIH R01-CA159859 (R.W.-R.) and a pilot project grant from the Medical College of Wisconsin Cancer Center–Advancing a Healthier Wisconsin (B.A.L.). R.W.-R. is the recipient of a Leadership Award (LA1-01747) from the California Institute of Regenerative Medicine. We thank the Stanford Functional Genomics Facility (SFGF) and the Protein and Nucleic Acid (PAN) facility for their assistance in generating gene expression microarray data and reagents. We thank M. Scott (Stanford), C. Rudin (Memorial Sloan-Kettering Cancer Center), P. Beachy (Stanford), A. Sweet-Cordero (Stanford), P.-T. Chang (University of California, San Francisco), R. Karlstrom (University of Massachusetts, Amherst) and J.K. Chen (Stanford) for reagents, helpful suggestions and/or critical reading of the manuscript.",
year = "2014",
month = jul,
doi = "10.1038/nm.3613",
language = "English (US)",
volume = "20",
pages = "732--740",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "7",
}