Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint

Abstract

The hSNF5 subunit of human SWI/SNF ATP-dependent chromatin remodeling complexes is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). Here, we report that loss of hSNF5 function in MRT-derived cells leads to polyploidization and chromosomal instability. Re-expression of hSNF5 restored the coupling between cell cycle progression and ploidy checkpoints. In contrast, cancer-associated hSNF5 mutants harboring specific single amino acid substitutions exacerbated poly-and aneuploidization, due to abrogated chromosome segregation. We found that hSNF5 activates the mitotic checkpoint through the p16 INK4a-cyclinD/CDK4-pRb-E2F pathway. These results establish that poly-and aneuploidy of tumor cells can result from mutations in a chromatin remodeler. Received January 12, 2005; revised version accepted January 27, 2005. ATP-dependent chromatin remodeling factors are critical components of the elaborate machinery that controls gene expression in eukaryotic cells (Becker and Horz 2002). The multisubunit SWI/SNF complex is the prototypical chromatin remodeling factor, present in all eukaryotes (Mohrmann and Verrijzer 2005). Human SNF5 (hSNF5, also known as Ini1, Baf47, or SmarcB1) encodes for a universal SWI/SNF subunit and tumor suppressor that is mutated in malignant rhabdoid tumors (MRTs) (Versteege et al. 1998;Klochendler-Yeivin et al. 2002;Roberts and Orkin 2004). MRTs are rare but highly aggressive pediatric cancers with a high mortality rate.Carriers of germline mutations are predisposed to various cancers and, consistent with a classic tumor suppressor phenotype, the wild-type allele is either lost or deleted in a large proportion of tumors (Biegel et al. 1999; Sevenet et al. 1999a,b;Taylor et al. 2000). hSNF5 mutations are also associated with a number of neoplasms other than MRTs (Grand et al. 1999; Sevenet et al. 1999a,b;Roberts and Orkin 2004). SNF5 inactivation studies in mice established its requirement during early embryogenesis and its role as a tumor suppressor (Klochendler-Yeivin et al. 2000;Roberts et al. 2000;Guidi et al. 2001;Roberts et al. 2002).Several studies found that re-expression of hSNF5 in MRT-derived cell lines caused an accumulation in G0/ G1, cellular senescence, and apoptosis (Ae et al. 2002;Betz et al. 2002;Versteege et al. 2002;Zhang et al. 2002;Oruetxebarria et al. 2004). These effects are largely the result of direct transcriptional activation of the tumor suppressor p16INK4a by hSNF5, which appears to be both necessary and sufficient for reduced cell proliferation and induction of cellular senescence and apoptosis (Oruetxebarria et al. 2004). p16INK4a controls the activity of pRb via inhibition of the cyclin D1-CDK4 kinase, which phosphorylates pRb (Lowe and Sherr 2003). Tumor suppressor pRb is a corepressor that is tethered to a broad range of genes by the E2F transcription factors. Hyperphosphorylation of pRb causes its dissociation from E2F, and relieves its antiproliferative activities. In addition to genes required for cell cycle progression from G1 to...

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

“…3, 4), a highly aggressive neoplasm affecting renal or extra-renal soft tissue, and cerebral tissue in pediatric patients. Previously published studies indicate that SMARCB1/INI1 gene is involved in the control of genomic stability and in the regulation of cell-cycle progression (5). SMARCB1 stimulates the p16/Rb tumor suppressor pathway by activation of CDKN2A and inhibition of Cdk/cyclinD (6).…”

The requirement for SNF5/INI1 in adipocyte differentiation highlights new features of malignant rhabdoid tumors

“…This hSNF5/INI1-induced cell-cycle arrest requires a functional RB/E2F pathway and is reversible (Medjkane et al, 2004). In addition to its role in the G 1 /S transition, the loss-of-function of hSNF5/INI1 disturbs mitotic checkpoint control and induces subsequent chromosomal instability (Vries et al, 2005). The tumor suppressor role of the SNF5/ INI1 subunit may not be limited to cell-cycle regulation but may also rely on cytoskeleton organization and DNA damage signaling (Medjkane et al, 2004;Klochendler-Yeivin et al, 2006).…”

Targeting cyclin D1, a downstream effector of INI1/hSNF5, in rhabdoid tumors

“…The majority of RTs harbor critical inactivating biallelic alterations in the INI1/hSNF5 gene, a tumor suppressor and a component of chromatin remodeling SWI/SNF complex (Versteege et al, 1998). Mechanisms of INI1/hSNF5-mediated tumor suppression include induction of G1 arrest and control of the mitotic spindle checkpoint (Ae et al, 2002;Betz et al, 2002;Versteege et al, 2002;Zhang et al, 2002;Vries et al, 2005).…”