RhoA-Dependent regulation of cell migration by the tumor suppressor hSNF5/INI1

Malignant rhabdoid tumors (MRT) are extremely aggressive pediatric tumors caused by the inactivation of the hSAW51INII tumor suppressor gene, which encodes a core member of the SWl/SNF chromatin remodeling complex. Roles for hSNF51 LVII in cell cycle and differentiation have been documented. Based on the observation that MRTs are highly invasive, we investigated a role for hSAW51INII in cell migration. MRT cell lines exhibit high migration properties that are dramatically reduced upon hSNF51INII 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 hSNF51INII 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/INII-mediated inhibition of migration, and that a missense mutation (S284L) associated with cancer is sufficient to impair hSNF5/INII function in migration. We conclude that the inhibition of migration is another crucial tumor suppressor function of hSNF51INII, 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.