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Mol Cancer Res. 2014 Nov;12(11):1574-85. doi: 10.1158/1541-7786.MCR-14-0005. Epub 2014 Jul 9.

SNF5/INI1 deficiency redefines chromatin remodeling complex composition during tumor development.

Author information

1
Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina.
2
Department of Computer Science, University of North Carolina at Chapel Hill, North Carolina.
3
Oncology Center, ZhuJiang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
4
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina.
5
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
6
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina.
7
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina. weissman@med.unc.edu kuwahara@koto.kpu-m.ac.jp.
8
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan. weissman@med.unc.edu kuwahara@koto.kpu-m.ac.jp.

Abstract

Malignant rhabdoid tumors (MRT), a pediatric cancer that most frequently appears in the kidney and brain, generally lack SNF5 (SMARCB1/INI1), a subunit of the SWI/SNF chromatin-remodeling complex. Recent studies have established that multiple SWI/SNF complexes exist due to the presence or absence of different complex members. Therefore, the effect of SNF5 loss upon SWI/SNF complex formation was investigated in human MRT cells. MRT cells and primary human tumors exhibited reduced levels of many complex proteins. Furthermore, reexpression of SNF5 increased SWI/SNF complex protein levels without concomitant increases in mRNA. Proteomic analysis, using mass spectrometry, of MRT cells before and after SNF5 reexpression indicated the recruitment of different components into the complex along with the expulsion of others. IP-Western blotting confirmed these results and demonstrated similar changes in other MRT cell lines. Finally, reduced expression of SNF5 in normal human fibroblasts led to altered levels of these same complex members. These data establish that SNF5 loss during MRT development alters the repertoire of available SWI/SNF complexes, generally disrupting those associated with cellular differentiation. These findings support a model where SNF5 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones. Therefore, restoration of these complexes in tumors cells provides an attractive approach for the treatment of MRTs.

IMPLICATIONS:

SNF5 loss dramatically alters SWI/SNF complex composition and prevents formation of complexes required for cellular differentiation.

PMID:
25009291
PMCID:
PMC4233162
DOI:
10.1158/1541-7786.MCR-14-0005
[Indexed for MEDLINE]
Free PMC Article

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