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PMID: 21076395 Published · ppublish English Journal Article

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

Nature medicine ·Vol. 16 ·No. 12 ·2010-12-00 ·Pages 1429-33

Jagani Z, Mora-Blanco EL, Sansam CG, McKenna ES, Wilson B, Chen D, Klekota J, Tamayo P, Nguyen PT, 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 CW, Dorsch M

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.

MeSH Terms
Animals Cell Line, Tumor Chromatin Immunoprecipitation Chromosomal Proteins, Non-Histone/genetics,metabolism DNA Primers/genetics DNA-Binding Proteins/genetics,metabolism Gene Expression Profiling Gene Expression Regulation, Neoplastic/genetics Humans Immunoblotting In Situ Hybridization Mass Spectrometry Mice Microarray Analysis Rhabdoid Tumor/genetics SMARCB1 Protein Signal Transduction/genetics Transcription Factors/genetics,metabolism Zinc Finger Protein GLI1
Chemicals
Chromosomal Proteins, Non-Histone DNA Primers DNA-Binding Proteins GLI1 protein, human SMARCB1 Protein SMARCB1 protein, human Transcription Factors Zinc Finger Protein GLI1
Authors & Affiliations
25 authors, click to expand affiliations / ORCID
Jagani Zainab
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
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
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2251
Published
2010-12-00
Epub
2010-00-14
Pages
1429-33
Language
English
Region
United States
NLM ID
9502015
PMCID
PMC3859448
Subset
IM
Grants
NCI NIH HHS · R01 CA109467 · United States
NCI NIH HHS · R01 CA113794 · United States
NCI NIH HHS · R01 CA121941 · United States
Corrections
CommentIn
PMID: 21135845
External Links
PubMed source DOI: 10.1038/nm.2251 PMC Full Text View journal details
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