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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    • "SNF5 has been shown to be directly recruited to target gene promoters and to suppress gene transcription by modification of the adjacent chromatin structure [14], [19], [20], [31]. To determine whether FGFR expression is controlled by SNF5 in a similar fashion we analyzed SNF5 localization to the FGFR2 promoter in BJ cells by chromatin immunoprecipitation (ChIP). "
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    PLoS ONE 10/2013; 8(10):e77652. DOI:10.1371/journal.pone.0077652 · 3.23 Impact Factor
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    • "In a mouse model with transgenic SMARCB1 mutation with biallelic somatic inactivation of NF2, there is activation of the cyclin D1 and mTOR pathways. Possible additional molecular drug targets are those deregulated due to loss of SMARCB1, including mitotic genes, PLK1 and Aurora A that are upregualted/de-repressed in tumors, and interferon pathway [Lee et al., 2011]. Hence, the pathways consisting of cyclin D1, PLK1, Aurora A, p16, and interferons are all possible targets for tumors harboring SMARCB1 mutations. "
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