Loss of the tumor suppressor snf5 leads to aberrant activation of the hedgehog-gli pathway

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. Access through your institution Buy or subscribe This is a preview of

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Scholar  Download references 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). AUTHOR INFORMATION Author notes * Marion Dorsch Present address: Present address: Sanofi-Aventis, Cambridge, Massachusetts, USA., *

Charles W M Roberts and Marion Dorsch: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * 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 *

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 * Broad Institute of Harvard and M.I.T, Cambridge, Massachusetts, USA Pablo Tamayo, Yoon-Jae Cho & 

Jill P Mesirov * Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA Michael Tolstorukov & Peter J Park * Department of Neurology, Children's

Hospital Boston, Boston, Massachusetts, USA Yoon-Jae Cho & Scott L Pomeroy * Novartis Institutes for BioMedical Research, Basel, Switzerland Heinz Ruffner & Tewis Bouwmeester Authors

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author inPubMed Google Scholar * Marion Dorsch View author publications You can also search for this author inPubMed Google Scholar 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. ETHICS DECLARATIONS

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). SUPPLEMENTARY

INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–11 and Supplementary Methods (PDF 1013 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE 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 Download citation * Received: 25 March 2010 * Accepted: 30 September 2010 * Published: 14 November 2010 * Issue Date: December 2010 * DOI:

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