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Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition

Nature Medicine volume 20, pages 732–740 (2014)Cite this article

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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.

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Figure 1: BRD4 is necessary for GLI transcription.
Figure 2: JQ1 inhibits Hh target gene activation at the level of the GLI1 and GLI2 promoters.
Figure 3: JQ1 inhibits Hh pathway activity and cell viability and proliferation in Ptch-mutated medulloblastoma (SmoWT-MB and Med1-MB) cells.
Figure 4: On-target validation of the inhibitory effects of JQ1 in Hh-driven tumor cells.
Figure 5: JQ1 inhibits Hh pathway activity and cell viability and proliferation in SMOi-resistant Hh-driven tumors.
Figure 6: JQ1 inhibits Hh-driven tumor growth in vivo.

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Acknowledgements

This work was supported the St. Baldrick'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'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.

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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA

    Yujie Tang, Simone Schubert, Sabran Masoud, Brian Nguyen, Nujsaubnusi Vue, Brianna Balansay, Furong Yu, Sekyung Oh, Pamelyn Woo, Spenser Chen, Anitha Ponnuswami, Michelle Monje & Yoon-Jae Cho

  2. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA

    Yujie Tang, Sharareh Gholamin, Simone Schubert, Furong Yu, Sekyung Oh, Siddhartha Mitra, Samuel H Cheshier & Yoon-Jae Cho

  3. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Minde I Willardson & Brian A Link

  4. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA

    Alex Lee, Scott X Atwood, Ramon J Whitson, Jean Y Tang & Anthony E Oro

  5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Pratiti Bandopadhayay, Guillame Bergthold, Rameen Beroukhim & James E Bradner

  6. Department of Pediatric Oncology, Pediatric Neuro-oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Pratiti Bandopadhayay & Guillame Bergthold

  7. Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA

    Pratiti Bandopadhayay & Guillame Bergthold

  8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Pratiti Bandopadhayay, Rameen Beroukhim & James E Bradner

  9. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Jun Qi, Rameen Beroukhim & James E Bradner

  10. Sanford-Burnham Medical Research, La Jolla, California, USA

    Rob Wechsler-Reya

  11. Stanford Cancer Institute, Stanford University Medical Center, Stanford, California, USA

    Yoon-Jae Cho

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  1. Yujie Tang
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Contributions

Y.T. and Y.-J.C. conceived the project and wrote the manuscript. Y.T., B.N., S.M., B.B., N.V., S.S., S.C., A.P., S.O. and F.Y. performed all molecular biology experiments. J.Q. and J.E.B. synthesized and supplied JQ1 for all studies. A.E.O., S.X.A., R.J.W., A.L. and J.Y.T. generated and prepared GEMM-derived BCC cells, and R.W.-R. generated and provided patient-derived medulloblastoma cells. P.B., G.B., R.B. and Y.-J.C. performed all informatics analyses. S.G., A.L., Y.T., S.M., P.W., M.M., S.H.C. and S.S. performed JQ1 mouse in vivo studies. M.I.W. and B.A.L. performed all zebrafish studies.

Corresponding author

Correspondence to Yoon-Jae Cho.

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Competing interests

The Dana-Farber Cancer Institute has licensed drug-like derivatives of JQ1 prepared in the Bradner laboratory to Tensha Therapeutics for clinical translation as cancer therapeutics. Dana-Farber and J.E.B. have been provided minority equity shares in Tensha. J.Q. has a consultant agreement with Tensha Therapeutics.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 3270 kb)

Supplementary Data Set

ssGSEA of gene expression data generated from SmoWT MB cells exposed for 6h to DMSO, JQ1 (1 μM), or GDC-0449 (0.1 μM) using v2.0 CGP gene sets (http://www.broadinstitute.org/gsea/msigdb/index.jsp). (TXT 830 kb)

Supplementary Table 1

Gene sets derived from Lee et al., PNAS 2010. (XLSX 23 kb)

Supplementary Table 2

qPCR primers used in study. (XLSX 9 kb)

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Tang, Y., Gholamin, S., Schubert, S. et al. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med 20, 732–740 (2014). https://doi.org/10.1038/nm.3613

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