Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Yujie Tang, Sharareh Gholamin, Simone Schubert, Minde I. Willardson, Alex Lee, Pratiti Bandopadhayay, Guillame Bergthold, Sabran Masoud, Brian Nguyen, Nujsaubnusi Vue, Brianna Balansay, Furong Yu, Sekyung Oh, Pamelyn Woo, Spenser Chen, Anitha Ponnuswami, Michelle Monje, Scott X. Atwood, Ramon J. Whitson, Siddhartha MitraSamuel H. Cheshier, Jun Qi, Rameen Beroukhim, Jean Y. Tang, Rob Wechsler-Reya, Anthony E. Oro, Brian A. Link, James E. Bradner, Yoon Jae Cho

Research output: Contribution to journalArticle

165 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)732-740
Number of pages9
JournalNature medicine
Volume20
Issue number7
DOIs
StatePublished - Jul 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Tang, Y., Gholamin, S., Schubert, S., Willardson, M. I., Lee, A., Bandopadhayay, P., Bergthold, G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Woo, P., Chen, S., Ponnuswami, A., Monje, M., Atwood, S. X., Whitson, R. J., ... Cho, Y. J. (2014). Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nature medicine, 20(7), 732-740. https://doi.org/10.1038/nm.3613