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Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5
Zhi-Kai Zhang1, Kelvin P Davies, Jeffrey Allen
1Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex and a tumor suppressor gene of aggressive pediatric atypical teratoid and malignant rhabdoid tumors (AT/RT). To understand the molecular mechanisms underlying its tumor suppressor function, we studied the effect of reintroduction of INI1/hSNF5 into AT/RT-derived cell lines such as MON that carry biallelic deletions of the INI1/hSNF5 locus. We demonstrate that expression of INI1/hSNF5 causes G(0)-G(1) arrest and flat cell formation in these cells. In addition, INI1/hSNF5 repressed transcription of cyclin D1 gene in MON, in a histone deacetylase (HDAC)-dependent manner. Chromatin immunoprecipitation studies revealed that INI1/hSNF5 was directly recruited to the cyclin D1 promoter and that its binding correlated with recruitment of HDAC1 and deacetylation of histones at the promoter. Analysis of INI1/hSNF5 truncations indicated that cyclin D1 repression and flat cell formation are tightly correlated. Coexpression of cyclin D1 from a heterologous promoter in MON was sufficient to eliminate the INI1-mediated flat cell formation and cell cycle arrest. Furthermore, cyclin D1 was overexpressed in AT/RT tumors. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. Repression of cyclin D1 gene expression may serve as a useful strategy to treat AT/RT.
Insights
INI1/hSNF5, a tumor suppressor, halts AT/RT cell growth by repressing cyclin D1 via HDAC recruitment. Restoring INI1/hSNF5 expression in AT/RT cells induces cell cycle arrest and flat cell formation.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- INI1/hSNF5 is a tumor suppressor crucial for pediatric atypical teratoid and malignant rhabdoid tumors (AT/RT).
- Understanding INI1/hSNF5's tumor suppressor mechanisms is vital for AT/RT treatment strategies.
Purpose of the Study:
- To elucidate the molecular mechanisms of INI1/hSNF5's tumor suppressor function in AT/RT.
- To investigate the role of INI1/hSNF5 in cell cycle regulation and gene expression.
Main Methods:
- Reintroduction of INI1/hSNF5 into AT/RT-derived cell lines (MON).
- Analysis of cell cycle progression (G(0)-G(1) arrest) and cell morphology.
- Chromatin immunoprecipitation (ChIP) to assess INI1/hSNF5 and HDAC1 recruitment to the cyclin D1 promoter.
- Histone deacetylase (HDAC) activity assays and cyclin D1 expression analysis.
Main Results:
- INI1/hSNF5 reintroduction induced G(0)-G(1) cell cycle arrest and flat cell formation in MON cells.
- INI1/hSNF5 repressed cyclin D1 gene transcription in a manner dependent on HDAC activity.
- INI1/hSNF5 directly recruited HDAC1 to the cyclin D1 promoter, leading to histone deacetylation and gene repression.
- Overexpression of cyclin D1 in AT/RT tumors was observed, and its reintroduction reversed INI1-mediated effects.
Conclusions:
- INI1/hSNF5 exerts tumor suppressor functions by recruiting HDAC activity to the cyclin D1 promoter, causing repression and G(0)-G(1) arrest.
- Cyclin D1 repression is a key mechanism underlying INI1/hSNF5's anti-tumorigenic effects in AT/RT.
- Targeting cyclin D1 expression may represent a therapeutic strategy for AT/RT.