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Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway

Nature Medicine volume 16, pages 1429–1433 (2010)Cite this article

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Abstract

Aberrant activation of the Hedgehog (Hh) pathway can drive tumorigenesis1. To investigate the mechanism by which glioma-associated oncogene family zinc finger-1 (GLI1), a crucial effector of Hh signaling2, regulates Hh pathway activation, we searched for GLI1-interacting proteins. We report that the chromatin remodeling protein SNF5 (encoded by SMARCB1, hereafter called SNF5), which is inactivated in human malignant rhabdoid tumors (MRTs), interacts with GLI1. We show that Snf5 localizes to Gli1-regulated promoters and that loss of Snf5 leads to activation of the Hh-Gli pathway. Conversely, re-expression of SNF5 in MRT cells represses GLI1. Consistent with this, we show the presence of a Hh-Gli–activated gene expression profile in primary MRTs and show that GLI1 drives the growth of SNF5-deficient MRT cells in vitro and in vivo. Therefore, our studies reveal that SNF5 is a key mediator of Hh signaling and that aberrant activation of GLI1 is a previously undescribed targetable mechanism contributing to the growth of MRT cells.

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Figure 1: Snf5 interacts with GLI1 and localizes to Gli1 regulated promoters.
Figure 2: Loss of Snf5 leads to activation of the Hh-Gli pathway in vitro and in vivo.
Figure 3: The Hh-Gli pathway is activated in MRT cell lines and primary tumors.
Figure 4: Inhibition of GLI1 impairs proliferation of MRT cells.

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Acknowledgements

We thank X. Wang, A. Bouret, J. DaSilva and A. Carlson for their assistance and S. S. Kadam for critical advice. The Gli1 probe was generously provided by C. Tabin (Harvard University Medical School).

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Author notes

  1. Marion Dorsch

    Present address: Present address: Sanofi-Aventis, Cambridge, Massachusetts, USA.,

  2. Charles W M Roberts and Marion Dorsch: These authors contributed equally to this work.

Authors and Affiliations

  1. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA

    Zainab Jagani, Dongshu Chen, Justin Klekota, Kathy Hsiao, Silvia Buonamici, Sarah J Luchansky, Joshua Murtie, Joseph F Kelleher, Markus Warmuth, William R Sellers & Marion Dorsch

  2. Department of Pediatric Oncology, Division of Hematology/Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston, Boston, Massachusetts, USA

    E Lorena Mora-Blanco, Courtney G Sansam, Elizabeth S McKenna, Boris Wilson, Phuong T L Nguyen & Charles W M Roberts

  3. Broad Institute of Harvard and M.I.T, Cambridge, Massachusetts, USA

    Pablo Tamayo, Yoon-Jae Cho & Jill P Mesirov

  4. Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA

    Michael Tolstorukov & Peter J Park

  5. Department of Neurology, Children's Hospital Boston, Boston, Massachusetts, USA

    Yoon-Jae Cho & Scott L Pomeroy

  6. Novartis Institutes for BioMedical Research, Basel, Switzerland

    Heinz Ruffner & Tewis Bouwmeester

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Contributions

Z.J. initiated the studies, conducted most of the experiments, analyzed data and wrote the manuscript. E.L.M.-B. conducted the Gli1 in situ experiments. C.G.S. generated Snf5-inactivated MEFs. E.S.M. contributed to Snf5 re-expression studies. B.W. assisted with ChIP studies. D.C. and J.M. conducted in vivo experiments. J.K. performed statistical analysis from interaction screen. P.T., Y.-J.C., J.P.M. and S.L.P. contributed to the gene expression analysis. M.T. and P.J.P. performed nucleosome repositioning assays. H.R., T.B., S.J.L. and J.F.K. contributed to the TAP-protein interaction screen. P.T.L.N. contributed to GLI shRNA studies. K.H. generated vectors for GLI1 deletions. S.B. contributed to the writing of the manuscript. M.W., W.R.S., C.W.M.R. and M.D. supervised the studies, assisted in data analysis and contributed to the writing of the manuscript.

Corresponding authors

Correspondence to Charles W M Roberts or Marion Dorsch.

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Competing interests

Z.J., D.C., J.P.M., K.H., S.B., J.K., H.R., T.B., S.L., J.F.K., M.W., and W.R.S. are employees of the Novartis Institutes for BioMedical Research (NIBR).

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Jagani, Z., Mora-Blanco, E., Sansam, C. et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med 16, 1429–1433 (2010). https://doi.org/10.1038/nm.2251

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