Article

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

ABSTRACT

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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    • "To study the mechanism of RB1-mediated epigenetic regulation of cell proliferation, differentiation and survival, we have focused on BRG1 (SMARCA4), which is an ATPase subunit of the SWI/SNF complex involved in nucleosome mobilization during development and tumorigenesis (Dunaief et al., 1994). BRG1 can bind all three Rb family members (Dunaief et al., 1994), and genetic analysis of human tumors has suggested that BRG1 is a tumor suppressor (Reisman et al., 2009; Medina et al., 2008; Rodriguez-Nieto et al., 2011; Hargreaves and Crabtree, 2011). For example, it was reported that a subgroup of patients with childhood medulloblastomas had recurrent mutations in BRG1 (Robinson et al., 2012). "
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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.
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    • "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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