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

Zainab Jagani, E. Lorena Mora-Blanco, Courtney G. Sansam, Elizabeth S. McKenna, Boris Wilson, Dongshu Chen, Justin Klekota, Pablo Tamayo, Phuong T.L. Nguyen, Michael Tolstorukov, Peter J. Park, Yoon-Jae Cho, Kathy Hsiao, Silvia Buonamici, Scott L. Pomeroy, Jill P. Mesirov, Heinz Ruffner, Tewis Bouwmeester, Sarah J. Luchansky, Joshua MurtieJoseph F. Kelleher, Markus Warmuth, William R. Sellers, Charles W.M. Roberts, Marion Dorsch

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

Aberrant activation of the Hedgehog (Hh) pathway can drive tumorigenesis. To investigate the mechanism by which glioma-associated oncogene family zinc finger-1 (GLI1), a crucial effector of Hh signaling, 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.

Original languageEnglish (US)
Pages (from-to)1429-1434
Number of pages6
JournalNature medicine
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

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Rhabdoid Tumor
Tumors
Chemical activation
Neoplasms
Chromatin Assembly and Disassembly
Zinc Fingers
Growth
Oncogenes
Transcriptome
Gene expression
Glioma
Chromatin
Zinc
Carcinogenesis
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Jagani, Z., Mora-Blanco, E. L., Sansam, C. G., McKenna, E. S., Wilson, B., Chen, D., ... Dorsch, M. (2010). Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nature medicine, 16(12), 1429-1434. https://doi.org/10.1038/nm.2251

Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. / Jagani, Zainab; Mora-Blanco, E. Lorena; Sansam, Courtney G.; McKenna, Elizabeth S.; Wilson, Boris; Chen, Dongshu; Klekota, Justin; Tamayo, Pablo; Nguyen, Phuong T.L.; Tolstorukov, Michael; Park, Peter J.; Cho, Yoon-Jae; Hsiao, Kathy; Buonamici, Silvia; Pomeroy, Scott L.; Mesirov, Jill P.; Ruffner, Heinz; Bouwmeester, Tewis; Luchansky, Sarah J.; Murtie, Joshua; Kelleher, Joseph F.; Warmuth, Markus; Sellers, William R.; Roberts, Charles W.M.; Dorsch, Marion.

In: Nature medicine, Vol. 16, No. 12, 01.12.2010, p. 1429-1434.

Research output: Contribution to journalArticle

Jagani, Z, Mora-Blanco, EL, Sansam, CG, McKenna, ES, Wilson, B, Chen, D, Klekota, J, Tamayo, P, Nguyen, PTL, Tolstorukov, M, Park, PJ, Cho, Y-J, Hsiao, K, Buonamici, S, Pomeroy, SL, Mesirov, JP, Ruffner, H, Bouwmeester, T, Luchansky, SJ, Murtie, J, Kelleher, JF, Warmuth, M, Sellers, WR, Roberts, CWM & Dorsch, M 2010, 'Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway', Nature medicine, vol. 16, no. 12, pp. 1429-1434. https://doi.org/10.1038/nm.2251
Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D et al. Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nature medicine. 2010 Dec 1;16(12):1429-1434. https://doi.org/10.1038/nm.2251
Jagani, Zainab ; Mora-Blanco, E. Lorena ; Sansam, Courtney G. ; McKenna, Elizabeth S. ; Wilson, Boris ; Chen, Dongshu ; Klekota, Justin ; Tamayo, Pablo ; Nguyen, Phuong T.L. ; Tolstorukov, Michael ; Park, Peter J. ; Cho, Yoon-Jae ; Hsiao, Kathy ; Buonamici, Silvia ; Pomeroy, Scott L. ; Mesirov, Jill P. ; Ruffner, Heinz ; Bouwmeester, Tewis ; Luchansky, Sarah J. ; Murtie, Joshua ; Kelleher, Joseph F. ; Warmuth, Markus ; Sellers, William R. ; Roberts, Charles W.M. ; Dorsch, Marion. / Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. In: Nature medicine. 2010 ; Vol. 16, No. 12. pp. 1429-1434.
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