p16INK4a Is Required for hSNF5 Chromatin Remodeler-induced Cellular Senescence in Malignant Rhabdoid Tumor Cells

Molecular Cell Biology Group , Leiden University, Leyden, South Holland, Netherlands
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2004; 279(5):3807-16. DOI: 10.1074/jbc.M309333200
Source: PubMed


The hSNF5 chromatin-remodeling factor is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). A number of studies have shown that hSNF5 re-expression blocks MRT cell proliferation. However, the pathway through which hSNF5 acts remains unknown. To address this question, we generated MRT-derived cell lines in which restoration of hSNF5 expression leads to an accumulation in G(0)/G(1), induces cellular senescence and increased apoptosis. Following hSNF5 expression, we observed transcriptional activation of the tumor suppressor p16(INK4a) but not of p14(ARF), repression of several cyclins and CD44, a cell surface glycoprotein implicated in metastasis. Chromatin immunoprecipitations indicated that hSNF5 activates p16(INK4a) transcription and CD44 down-regulation by mediating recruitment of the SWI/SNF complex. Thus, hSNF5 acts as a dualistic co-regulator that, depending on the promoter context, can either mediate activation or repression. Three lines of evidence established that p16(INK4a) is an essential effector of hSNF5-induced cell cycle arrest. 1) Overexpression of p16(INK4a) mimics the effect of hSNF5 induction and leads to cellular senescence. 2) Expression of a p16(INK4a)-insensitive form of CDK4 obstructs hSNF5-induced cell cycle arrest. 3) Inhibition of p16(INK4a) activation by siRNA blocks hSNF5-mediated cellular senescence. Collectively, these results indicate that in human MRT cells, the p16(INK4a)/pRb, rather than the p14(ARF)/p53 pathway, mediates hSNF5-induced cellular senescence.

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    • "By rendering the genome more or less accessible for the transcriptional regulatory machinery, the SWI/SNF complex has both repressive and activating functions in the regulation of gene expression [7]–[9]. SNF5 does not contain any DNA-binding motifs, but has been shown to form manifold interactions with transcription factors and DNA-regulatory proteins, such as GLI1, c-MYC, MLL/ALL-1, GADD43 and p53 [10]–[14] and has been implicated in the recruitment of the SWI/SNF complex to specific target gene promoters [15]. In particular, SNF5 has a critical function in cell cycle control and affects the pRb tumor suppressor pathway by inducing expression of p16INK4A and repression of cyclin D1 [16]–[18]. "
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    ABSTRACT: Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.
    PLoS ONE 10/2013; 8(10):e77652. DOI:10.1371/journal.pone.0077652 · 3.23 Impact Factor
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    • "This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors (Oruetxebarria, Venturini et al. 2004; Martinez- Glez, Franco-Hernandez et al. 2008). In addition, the LARGE gene (22q12.3) "

    Tumor Suppressor Genes, 02/2012; , ISBN: 978-953-307-879-3
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    • "Indeed, loss of heterozygosity of SNF5 predisposes mice to cancer development at a high frequency (Guidi et al. 2001; Klochendler-Yeivin et al. 2000; Roberts et al. 2000). In addition, conditional inactivation of SNF5 in hematopoietic tissues resulted in an extremely rapid onset of CD8+ lymphomas (Roberts et al. 2002), potentially via transcriptional activation of p16 and inhibition of cyclin D1 (Chai et al. 2007; Oruetxebarria et al. 2004; Vries et al. 2005; Zhang et al. 2002). "
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    ABSTRACT: SNF5, a core component of the SWI/SNF chromatin remodeling complex, is expressed as two isoforms, SNF5a and SNF5b. SNF5 is a tumor suppressor, as mutation of SNF5 leads to tumor formation and cooperates with p53 deficiency to enhance cancer susceptibility. Interestingly, lack of SNF5 inhibits cell survival and embryonic development, potentially through abnormal activation of p53. To further examine this, we generated cell lines in which SNF5a, SNF5b or both can be inducibly knocked down. We found that SNF5 knockdown leads to cell-cycle arrest in G(1), and SNF5a and SNF5b are functionally redundant. We also showed that SNF5 knockdown impairs p53-dependent transcription of p21 and murine double minute 2. However, contrary to earlier reports that p53 is activated by SNF5 knockout in murine cells, SNF5 knockdown leads to decreased, but not increased, expression of both basal and stress-induced p53 in multiple human cell lines. In addition, we showed that SNF5 knockdown induces adenosine monophosphate-activated protein kinase activation and inhibits eIF4E expression. Finally, we showed that SNF5 knockdown inhibits p53 translation by eIF4E and replacement of eIF4E in SNF5 knockdown cells restores p53 expression and cell survival. Together, our study results suggest that the p53 pathway is regulated by, and mediates the activity of, SNF5 in tumor suppression and prosurvival.
    Oncogene 07/2010; 29(28):4090-100. DOI:10.1038/onc.2010.159 · 8.46 Impact Factor
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