Aurora A Is a Repressed Effector Target of the Chromatin Remodeling Protein INI1/hSNF5 Required for Rhabdoid Tumor Cell Survival

Department of Genetics, Albert Einstein College of Medicine, New York University, New York, NY, USA.
Cancer Research (Impact Factor: 9.33). 05/2011; 71(9):3225-35. DOI: 10.1158/0008-5472.CAN-10-2167
Source: PubMed


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.

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Available from: Ganjam V Kalpana, Sep 23, 2015
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    • "Over the last few years, a number of transcription factors capable of modulating the expression of AURKA gene have been identified. These include the p53, the HIF-1, and the INI1/hSSNF5, all reported to negatively regulate the activity of the AURKA promoter [10–12]. Conversely, the transcriptional activity of the AURKA promoter has been shown to increase following the interaction with the ΔEGFR/STAT5 complex in glioblastoma cells [13]. "
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