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RhoA-Dependent Regulation of Cell Migration by the Tumor Suppressor hSNF5/INI1

Institut Curie and Institut National de la Santé et de la Recherche Medicale U830, Unité de Génétique et Biologie des Cancers, Paris, France

Requests for reprints: Olivier Delattre, Institut National de la Sante et de la Recherche Medicale U830, Unité de Génétique et Biologie des Cancers, Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France. Phone: 33-1-56-24-66-81; Fax: 33-1-56-24-66-30; E-mail: olivier.delattre{at}curie.fr.

Key Words: SNF5/INI1 • rhabdoid tumor suppressor • migration • SWI/SNF

Malignant rhabdoid tumors (MRT) are extremely aggressive pediatric tumors caused by the inactivation of the hSNF5/INI1 tumor suppressor gene, which encodes a core member of the SWI/SNF chromatin remodeling complex. Roles for hSNF5/INI1 in cell cycle and differentiation have been documented. Based on the observation that MRTs are highly invasive, we investigated a role for hSNF5/INI1 in cell migration. MRT cell lines exhibit high migration properties that are dramatically reduced upon hSNF5/INI1 expression. This effect is associated with the disorganization of the actin stress fiber network and is mediated by the inhibition of the activity of the small GTPase RhoA, through a nuclear, SWI/SNF-dependent transcriptional mechanism. We further show that the knockdown of hSNF5/INI1 in epithelial 293T or MCF7 cells results in increased cell size, loss of cell-cell adhesions, and enhanced migration, associated with an increased RhoA activity. Finally, we show that the SNF5 homology domain is required for hSNF5/INI1-mediated inhibition of migration, and that a missense mutation (S284L) associated with cancer is sufficient to impair hSNF5/INI1 function in migration. We conclude that the inhibition of migration is another crucial tumor suppressor function of hSNF5/INI1, in addition to its previously described functions in proliferation and differentiation, and that its loss-of-function in MRTs may account for the high invasiveness and metastatic potential of these tumors. [Cancer Res 2008;68(15):6154–61]

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