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Cancer Res. 2011 May 1;71(9):3225-35. doi: 10.1158/0008-5472.CAN-10-2167. Epub 2011 Apr 26.

Aurora A is a repressed effector target of the chromatin remodeling protein INI1/hSNF5 required for rhabdoid tumor cell survival.

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  • 1Department of Genetics, Albert Einstein College of Medicine, New York University, New York, NY, USA.

Abstract

Rhabdoid tumors (RT) are aggressive pediatric malignancies with poor prognosis. INI1/hSNF5 is a component of the chromatin remodeling SWI/SNF complex and a tumor suppressor deleted in RT. Previous microarray studies indicated that reintroduction of INI1/hSNF5 into RT cells leads to repression of a high degree of mitotic genes including Aurora Kinase A (Aurora A, STK6). Here, we found that INI1/SNF5 represses Aurora A transcription in a cell-type-specific manner. INI1-mediated repression was observed in RT and normal cells but not in non-RT cell lines. Chromatin immunoprecipitation (ChIP) assay indicated that INI1/hSNF5 associates with Aurora A promoter in RT and normal cells but not in non-RT cells. Real-time PCR and immunohistochemical analyses of primary human and mouse RTs harboring mutations in INI1/hSNF5 gene indicated that Aurora A was overexpressed/derepressed in these tumor cells, confirming that INI1/hSNF5 represses Aurora A in vivo. Knockdown of Aurora A impaired cell growth, induced mitotic arrest and aberrant nuclear division leading to decreased survival, and increased cell death and caspase 3/7-mediated apoptosis in RT cells (but not in normal cells). These results indicated that Aurora A is a direct downstream target of INI1/hSNF5-mediated repression in RT cells and that loss of INI1/hSNF5 leads to aberrant overexpression of Aurora A in these tumors, which is required for their survival. We propose that a high degree of Aurora A expression may play a role in aggressive behavior of RTs and that targeting expression or activity of this gene is a novel therapeutic strategy for these tumors.

PMID:
21521802
[PubMed - indexed for MEDLINE]
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