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

SeungJae Lee, Velasco Cimica, Nandini Ramachandra, David Zagzag, Ganjam V. Kalpana

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3225-3235
Number of pages11
JournalCancer Research
Volume71
Issue number9
DOIs
StatePublished - May 1 2011

Fingerprint

Rhabdoid Tumor
Chromatin Assembly and Disassembly
Cell Survival
Proteins
Neoplasms
Aurora Kinase A
Genes
Cell Nucleus Division
Caspase 7
Survival
Chromatin Immunoprecipitation
Tumor Cell Line
Caspase 3
Real-Time Polymerase Chain Reaction
Cell Death

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Aurora A is a repressed effector target of the chromatin remodeling protein INI1/hSNF5 required for rhabdoid tumor cell survival. / Lee, SeungJae; Cimica, Velasco; Ramachandra, Nandini; Zagzag, David; Kalpana, Ganjam V.

In: Cancer Research, Vol. 71, No. 9, 01.05.2011, p. 3225-3235.

Research output: Contribution to journalArticle

Lee, SeungJae ; Cimica, Velasco ; Ramachandra, Nandini ; Zagzag, David ; Kalpana, Ganjam V. / Aurora A is a repressed effector target of the chromatin remodeling protein INI1/hSNF5 required for rhabdoid tumor cell survival. In: Cancer Research. 2011 ; Vol. 71, No. 9. pp. 3225-3235.
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