ReviewSWI/SNF chromatin remodeling and cancer
Introduction
Histones serve a dual role in the nucleus of eukaryotic cells. First, they are assembled with DNA into nucleosomes that can form higher-order structures. Second, they establish a dynamic molecular interface and play an active role in the regulation of transcription. This regulation occurs at least in part by covalent modifications of the tails of core histones. Modifications such as acetylation, phosphorylation and methylation modulate the nucleosome structure and the interaction with activators and repressors. Furthermore, over the past few years, a growing number of studies have led to the identification of additional mechanisms that regulate chromatin function in conjunction with histone covalent modifications. These involve enzymatic complexes that remodel chromatin and serve as transcriptional co-factors (reviewed in [1]). One class of such co-factors is represented by the SWI/SNF remodeling complexes that alter the path of DNA around the nucleosomal histone core in an ATP-dependent manner, resulting in nucleosome mobilization (reviewed in [2]). First identified in the yeast Saccharomyces cerevisiae, SWI/SNF is a 2MDa multisubunit assembly that is highly conserved in eukaryotes. Mammalian SWI/SNF complexes contain one of the two potential catalytic ATPase subunits, Brm or Brg1. They further diverge biochemically in their subunit composition, suggesting that they might have specialized cellular functions [3]. Whereas chromatin-remodeling complexes are generally thought to promote gene expression, recent genetic and biochemical studies suggest that the SWI/SNF complex may also be involved in transcriptional repression 4., 5., 6., 7•.. The subunit composition of the different human complexes that belong to this family is listed in Table 1. Several of the subunits, including SNF5/INI1, are common to all complexes and may constitute its core.
Genetic alterations or dysregulated expression of genes involved in cell-cycle control, differentiation, cell death or maintenance of genomic integrity may be sufficient to drive malignant transformation. The precise transcriptional response to cellular regulatory circuits involves the core transcription machinery, gene-specific activators or repressors, as well as chromatin-remodeling activities that may either antagonize or enhance the repressive effects of chromatin. It is not difficult to imagine that balanced chromatin remodeling activities are crucial to ensure accurate responses to developmental or environmental cues, and to prevent the transition of normal cells into cancer cells. In this review, we describe recent genetic studies supporting the idea that the SWI/SNF complex is involved in tumor suppression. We also discuss protein interactions and functions focusing on the regulatory pathways of tumor suppressors and oncogenes.
Section snippets
Mutations in human primary tumors and tumor-derived cell lines
Accumulating molecular genetic evidence suggests that ATP-dependent chromatin remodeling by the SWI/SNF complex plays a crucial role in human tumorigenesis. Bi-allelic deletions or truncating mutations of SNF5/INI1/BAF47 on chromosome 22q11 were shown to be associated with most cases of malignant rhabdoid tumor. This rare but very aggressive pediatric cancer was initially described in the kidney, and subsequently reported as occurring elsewhere, including liver, lung and CNS where it is termed
Mouse models
The association of human malignancies with homozygous deletions or inactivating mutations of SNF5 and Brg1 suggested that SWI/SNF loss-of-function may contribute to oncogenesis in different cell types. The development of mouse models has provided further evidence that these critical components of the chromatin-remodeling machinery act as growth suppressors. Both SNF5 and Brg1 heterozygous mice display a cancer-prone phenotype. Several groups have shown recently that heterozygosity at the SNF5
The Rb connection
Early transfection studies (e.g. [22]) demonstrated that Brg1 and Brm can associate with the retinoblastoma protein (pRB) to induce growth arrest. More recently, LKB1, a serine-threonine kinase mutated in patients with Peutz–Jeghers Syndrome was found to interact with Brg1 and its kinase activity is necessary for Brg1/Rb-dependent cell-cycle arrest [23]. The Rb TSG plays a fundamental role in cell-cycle control, apoptosis and development. A major cellular target of pRB is the E2F family of
Conclusions
Genetic studies in human and mouse have shown that inactivating mutations or deletions of genes encoding subunits of the SWI/SNF complex are associated with cancer, qualifying these genes as putative tumor suppressors. Although there has been much focus on the role of the pRB pathway, biochemical and molecular studies have revealed an increasing number of potential targets of the SWI/SNF complex that function as either positive or negative regulators of cell growth. Thus, the SWI/SNF complex
Acknowledgements
We apologize to those whose work was not cited directly because of space constraints. We thank Jonathan Weitzman and Olivier Delattre for critical reading and advice on the manuscript. We thank the AICR Foundation, ARC and LNFCC for financial support.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
•of special interest
••of outstanding interest
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CRIF1 enhances p53 activity via the chromatin remodeler SNF5 in the HCT116 colon cancer cell lines
2017, Biochimica et Biophysica Acta - Gene Regulatory MechanismsLoss of expression of the SWI/SNF chromatin remodeling subunit BRG1/SMARCA4 is frequently observed in intraductal papillary mucinous neoplasms of the pancreas
2012, Human PathologyCitation Excerpt :This inhibition appears to be at least partly mediated by the suppression of cyclin E as an E2F target gene, and the overexpression of transcripts of cyclin-dependent kinase inhibitors p21 and p15 [35]. It has also been shown that BRG1 itself interacts with tumor suppressor proteins (eg, RB1, BRCA1) and components involved in Wnt signaling [24,38-44], suggesting a role for this gene not only in chromatin remodeling but also in cell-cycle regulation and in the activity of tumor-suppressor factors. The role of BRG1 in pancreatic carcinogenesis is poorly defined.
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