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 Murtie; Joseph F. Kelleher; Markus Warmuth; William R. Sellers; Charles W.M. Roberts; Marion Dorsch

doi:10.1038/nm.2251

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 journal › Article › peer-review

202 Scopus citations

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 language	English (US)
Pages (from-to)	1429-1434
Number of pages	6
Journal	Nature medicine
Volume	16
Issue number	12
DOIs	https://doi.org/10.1038/nm.2251
State	Published - Dec 2010
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Jagani, Z., Mora-Blanco, E. L., Sansam, C. G., McKenna, E. S., Wilson, B., Chen, D., Klekota, J., Tamayo, P., Nguyen, P. T. L., Tolstorukov, M., Park, P. J., Cho, Y. J., Hsiao, K., Buonamici, S., Pomeroy, S. L., Mesirov, J. P., Ruffner, H., Bouwmeester, T., Luchansky, S. J., ... 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

Jagani, Z, Mora-Blanco, EL, Sansam, CG, McKenna, ES, Wilson, B, Chen, D, Klekota, J, Tamayo, P, Nguyen, PTL, Tolstorukov, M, Park, PJ, Cho, YJ, 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

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title = "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 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.",

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

year = "2010",

month = dec,

doi = "10.1038/nm.2251",

language = "English (US)",

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AU - Jagani, Zainab

AU - Mora-Blanco, E. Lorena

AU - Sansam, Courtney G.

AU - McKenna, Elizabeth S.

AU - Wilson, Boris

AU - Chen, Dongshu

AU - Klekota, Justin

AU - Tamayo, Pablo

AU - Nguyen, Phuong T.L.

AU - Tolstorukov, Michael

AU - Park, Peter J.

AU - Cho, Yoon Jae

AU - Hsiao, Kathy

AU - Buonamici, Silvia

AU - Pomeroy, Scott L.

AU - Mesirov, Jill P.

AU - Ruffner, Heinz

AU - Bouwmeester, Tewis

AU - Luchansky, Sarah J.

AU - Murtie, Joshua

AU - Kelleher, Joseph F.

AU - Warmuth, Markus

AU - Sellers, William R.

AU - Roberts, Charles W.M.

AU - Dorsch, Marion

PY - 2010/12

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N2 - 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.

AB - 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.

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

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