The SWI/SNF complex and cancer. Oncogene

Department of Internal Medicine, University of Michigan College of Medicine, Ann Arbor, MI 48109-0686, USA.
Oncogene (Impact Factor: 8.46). 03/2009; 28(14):1653-68. DOI: 10.1038/onc.2009.4
Source: PubMed


The mammalian SWI/SNF complexes mediate ATP-dependent chromatin remodeling processes that are critical for differentiation and proliferation. Not surprisingly, loss of SWI/SNF function has been associated with malignant transformation, and a substantial body of evidence indicates that several components of the SWI/SNF complexes function as tumor suppressors. This review summarizes the evidence that underlies this conclusion, with particular emphasis upon the two catalytic subunits of the SWI/SNF complexes, BRM, the mammalian ortholog of SWI2/SNF2 in yeast and brahma in Drosophila, and Brahma-related gene-1 (BRG1).

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Available from: David Reisman, May 19, 2014
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    • "Neural progenitors require BAF45a/53a subunits to support proliferation, while differentiation to postmitotic neurons necessitates BAF45b/45c/53b (Lessard et al. 2007). The SWI/SNF family is widely known as a master regulator of gene expression, having roles in various pathways related to cell adhesion, alternative splicing, cell cycle regulation and differentiation (Reisman et al. 2009). Several members, including BRG1 and SNF5, are frequently mutated or silenced in various types of cancers, pointing to a possible function as a tumor suppressor (Clapier and Cairns 2009). "
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    ABSTRACT: The intestinal epithelium is an ideal model system for the study of normal and pathological differentiation processes. The mammalian intestinal epithelium is a single cell layer comprising proliferative crypts and differentiated villi. The crypts contain both proliferating and quiescent stem cell populations that self-renew and produce all the differentiated cell types, which are replaced every 3-5 days. The genetics of intestinal development, homeostasis, and disease are well defined, but less is known about the contribution of epigenetics in modulating these processes. Epigenetics refers to heritable phenotypic traits, including gene expression, which are independent of mutations in the DNA sequence. We have known for several decades that human colorectal cancers contain hypomethylated DNA, but the causes and consequences of this phenomenon are not fully understood. In contrast, tumor suppressor gene promoters are often hypermethylated in colorectal cancer, resulting in decreased expression of the associated gene. In this review, we describe the role that epigenetics plays in intestinal homeostasis and disease, with an emphasis on results from mouse models. We highlight the importance of producing and analyzing next-generation sequencing data detailing the epigenome from intestinal stem cell to differentiated intestinal villus cell.
    Cellular and Molecular Life Sciences CMLS 07/2015; DOI:10.1007/s00018-015-1997-9 · 5.81 Impact Factor
    • "SWI/SNF complexes are subdivided into PBAF and BAF complexes based on the presence of BAF250A or BAF250B (BAF complex ; contains either BRG1 or BRM ATPase) or BAF180 (PBAF complex; contains only BRG1 ATPase), although this distinction may not be absolute (Ryme et al. 2009; Wilson and Roberts 2011; Euskirchen et al. 2012). Importantly , inactivating mutations in several SWI/SNF components are found at high frequency in a variety of cancers, including breast cancer, implicating SWI/SNF in tumor suppression (Reisman et al. 2009; Wilson and Roberts 2011). We hypothesize that mutant p53 co-opts SWI/SNF complex function to mediate its gain-of-function transcriptional effects. "
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    ABSTRACT: Mutant p53 impacts the expression of numerous genes at the level of transcription to mediate oncogenesis. We identified vascular endothelial growth factor receptor 2 (VEGFR2), the primary functional VEGF receptor that mediates endothelial cell vascularization, as a mutant p53 transcriptional target in multiple breast cancer cell lines. Up-regulation of VEGFR2 mediates the role of mutant p53 in increasing cellular growth in two-dimensional (2D) and three-dimensional (3D) culture conditions. Mutant p53 binds near the VEGFR2 promoter transcriptional start site and plays a role in maintaining an open conformation at that location. Relatedly, mutant p53 interacts with the SWI/SNF complex, which is required for remodeling the VEGFR2 promoter. By both querying individual genes regulated by mutant p53 and performing RNA sequencing, the results indicate that >40% of all mutant p53-regulated gene expression is mediated by SWI/SNF. We surmise that mutant p53 impacts transcription of VEGFR2 as well as myriad other genes by promoter remodeling through interaction with and likely regulation of the SWI/SNF chromatin remodeling complex. Therefore, not only might mutant p53-expressing tumors be susceptible to anti VEGF therapies, impacting SWI/SNF tumor suppressor function in mutant p53 tumors may also have therapeutic potential. © 2015 Pfister et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 06/2015; 29(12). DOI:10.1101/gad.263202.115 · 10.80 Impact Factor
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    • "Some SWI/SNF subunits can participate to other multiprotein complexes also involved in gene transcription regulation, such as N-CoR, WINAC, NUMAC and mSIN3A [2], [4]. SWI/SNF remodeling activity is involved in many physiological processes such as embryonic development, maintenance of pluripotency, cell reprogramming [5], cellular differentiation and pathological processes like tumorigenesis or neurological disorders [6], [7]. Indeed, several SWI/SNF subunits, such as BRG1, BAF250, BAF180 and BAF47, are mutated in various cancer types and some are bona fide tumor suppressors, such as BAF47 [3], [6], [7]. "
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    ABSTRACT: Myogenic terminal differentiation is a well-orchestrated process starting with permanent cell cycle exit followed by muscle-specific genetic program activation. Individual SWI/SNF components have been involved in muscle differentiation. Here, we show that the master myogenic differentiation factor MyoD interacts with more than one SWI/SNF subunit, including the catalytic subunit BRG1, BAF53a and the tumor suppressor BAF47/INI1. Downregulation of each of these SWI/SNF subunits inhibits skeletal muscle terminal differentiation but, interestingly, at different differentiation steps and extents. BAF53a downregulation inhibits myotube formation but not the expression of early muscle-specific genes. BRG1 or BAF47 downregulation disrupt both proliferation and differentiation genetic programs expression. Interestingly, BRG1 and BAF47 are part of the SWI/SNF remodeling complex as well as the N-CoR-1 repressor complex in proliferating myoblasts. However, our data show that, upon myogenic differentiation, BAF47 shifts in favor of N-CoR-1 complex. Finally, BRG1 and BAF47 are well-known tumor suppressors but, strikingly, only BAF47 seems essential in the myoblasts irreversible cell cycle exit. Together, our data unravel differential roles for SWI/SNF subunits in muscle differentiation, with BAF47 playing a dual role both in the permanent cell cycle exit and in the regulation of muscle-specific genes.
    PLoS ONE 10/2014; 9(10):e108858. DOI:10.1371/journal.pone.0108858 · 3.23 Impact Factor
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