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Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Perturbations in Cancer Bernard Weissman1 and Karen E

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Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Perturbations in Cancer Bernard Weissman1 and Karen E Published OnlineFirst October 20, 2009; DOI: 10.1158/0008-5472.CAN-09-2166 Review Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Perturbations in Cancer Bernard Weissman1 and Karen E. Knudsen2 1Department of Pathology and Laboratory and Lineberger Cancer Center, University of North Carolina, Chapel Hill, North Carolina and 2Department of Cancer Biology, Department of Urology, and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania Abstract quently show differentially altered expression patterns and in vivo There is increasing evidence that alterations in chromatin re- functions. modeling play a significant role in human disease. The SWI/ Accompanying each ATPase are 10 to 12 proteins known as SNF chromatin remodeling complex family mobilizes nucleo- BAFs (BRG1- or BRM-associated factors) consisting of core and ac- somes and functions as a master regulator of gene expression cessory subunits (Fig. 1). The core subunits, BAF155, BAF170, and and chromatin dynamics whose functional specificity is driv- SNF5 (also referred to as SMARCB1, BAF47, or INI1), were func- en by combinatorial assembly of a central ATPase and associ- tionally classified on the basis of their ability to restore efficient ation with 10 to 12 unique subunits. Although the biochemical nucleosome remodeling in vitro (8, 9). BAF155 maintains a scaf- consequence of SWI/SNF in model systems has been extensive- folding-like function, and can influence both stability and assembly ly reviewed, the present article focuses on the evidence linking of other SWI/SNF subunits (10). The function of BAF170, which SWI/SNF perturbations to cancer initiation and tumor pro- shares homology with BAF155, is less well understood, but may gression in human disease. [Cancer Res 2009;69(21):8223–30] also control the levels of other SWI/SNF subunits. Given these activities, the roles of BAF155 and BAF170 as core subunits can be readily conceptualized. By contrast, the function of SNF5 is Introduction divergent, as this subunit contains an intrinsic, nonspecific, The SWI/SNF family of chromatin remodeling complexes are DNA-binding domain. Much emphasis has been placed on delin- master regulators of transcription factor action and resultant gene eation of SNF5 action, as this subunit is a bona fide tumor sup- expression programs. SWI/SNF complexes are large, ∼2-MDa mul- pressor gene in malignant rhabdoid tumor development, and ti-subunit conglomerates that serve to either enhance or suppress regulates expression of critical proliferative control genes (11, gene transcription through mobilization of nucleosomes (1, 2). In- 12). Thus, the core SWI/SNF subunits encompass widely distinct triguingly, mounting evidence supports the paradigm that specific- biochemical and functional activities. ity of SWI/SNF action evolves through combinatorial assembly of The accessory subunits are hypothesized to dictate specificity of 10 to 12 subunits, and that “imbalances” in subunit composition SWI/SNF complex function (1, 4). These subunits include BAF60a, are frequently observed in human cancers. Although the functions b, and c, encoded by three distinct genes and present in only one of SWI/SNF in transcriptional control and development have been copy per complex. The BAF45a-d and BAF53a and b accessory sub- extensively reviewed (1–6), the present study will focus exclusively unit classes are similarly encoded by multiple genes, but the rele- on the role of SWI/SNF and its subunit dysregulation in tumori- vance of each for overall SWI/SNF function and combinatorial genesis, disease progression, and therapeutic resistance. assembly remains incompletely defined. Established demonstra- tion of specificity arises from the BAF250a, b, and BAF180 subu- nits, which define the BAF and PBAF versions of SWI/SNF Diversity in SWI/SNF Composition: A Brief Overview complexes, respectively. BAF180 incorporation into SWI/SNF is SWI/SNF subunits can be grossly subclassified into three cate- mutually exclusive with the presence of BAF250a or BAF250b. Ad- gories: (i) enzymatic (ATPase), (ii) core subunits, and (iii) accessory ditional specificity factors with a suggested role in human disease subunits (7). Although the precise mechanisms by which SWI/SNF include BAF57, BAF200, BAF53a, and beta-actin. Overall, the rela- modifies chromatin structure remain incompletely understood, tive abundance and combinatorial assembly of these subunits has “ ” this process is thought to involve ATPase-dependent disruption been elegantly compared with a chromatin-remodeling language, “ ” of histone-DNA association and resultant nucleosome “sliding” wherein the subunit letters can be assembled into at least 288 (2, 7). Accordingly, each SWI/SNF complex incorporates one of distinct words, each with possible alternative cellular outcomes two possible ATPases, BRM (Brahma) or BRG1 (Brahma-Related (1). In keeping with this concept, specific SWI/SNF combinations Gene 1), which share 75% amino acid identity. On the basis of these have been recently implicated with pluripotency and therefore observations, it might be expected that the ATPases serve over- deemed esBAFs (13). By contrast, it is apparent in human cancer lapping cellular functions and follow similar disruption patterns that disease-associated misspellings can contribute to disease ini- in human disease. In contrast, laboratory and clinical evidence, tiation, progression, and metastasis. discussed within this article, suggest that the two ATPases fre- Cancer Initiation Requests for reprints: KarenE.Knudsen,ThomasJeffersonUniversity/KimmelCancer Incontrovertible evidence supports the contention that SWI/ Center, 233 South 10th Street, Bluemle Building- Room 1008, Philadelphia, PA 19107. Phone: SNF alterations contribute to tumorigenesis. Intriguingly, these al- 215-503-8574; Fax: 215-923-4498; E-mail: [email protected]. ©2009 American Association for Cancer Research. terations frequently entail tissue- and/or tumor-specific loss of in- doi:10.1158/0008-5472.CAN-09-2166 dividual subunits, resulting in elimination of specific SWI/SNF www.aacrjournals.org 8223 Cancer Res 2009; 69: (21). November 1, 2009 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst October 20, 2009; DOI: 10.1158/0008-5472.CAN-09-2166 Cancer Research Figure 1. SWI/SNF subunits. Distinct SWI/SNF complexes are formed by combinatorial assembly of a central ATPase (pink),the core subunits (green),and selected accessory subunits ( purple). Aliases and gene identifications for each known subunit are provided. complexes and possible creation of new combinatorial assemblies. lung cancer cell lines (36). Whether these results indicate that Although the biochemical consequence of SWI/SNF subunit loss is the reduced levels of BRG1 initiate tumor development in a rare currently under active investigation, SWI/SNF misregulation seems population of cells or promote tumor progression in a rare popu- to play a subunit- and tissue-specific role in cancer initiation lation of initiated cells remains unresolved, but they provide strong (Fig. 2). indication that BRG1 possesses tumor suppressor functions. ATPases: specialized tumor suppressors? Extensive analyses Despite the molecular similarities in function between BRG1 support tissue- and tumor-specific roles of SWI/SNF ATPase and BRM, the pattern and influence of BRM loss on tumorigenesis subunit loss in tumor development. Several reports have shown is largely distinct from that of BRG1. Disparity in requirement for mutations and/or loss of BRG1 in human cancer cell lines and pri- BRG1 versus BRM was first noted as a result of GEMM, in which it − − mary tumors (14–20). Supporting a role in cancer initiation, loss of was revealed that Brm / animals are viable, fertile, and slightly heterozygosity (LOH) of the region surrounding BRG (21) occurs larger than wild-type littermates (37). Closer examination led to with significant frequency in human adenocarcinomas (22–27). discovery of links between BRM loss and human disease. In the − − Interest in this region is heightened by the presence of the lung, exposure of Brm / animals to ethyl carbamate results in in- Peutz-Jeghers multiple adenocarcinoma syndrome gene, STK11/ creased development of lung adenomas, thus implicating a role for LKB1, which maps 8.5 Mb distally from BRG1 (Fig. 3; refs. 26–30). BRM loss in lung cancer development (16). Further supporting this Importantly, chromosome transfer studies mapped tumor suppres- premise, BRM is down-regulated in up to 30% of lung cancer cell sor function to this region (31, 32), and at least one report localized lines analyzed, and is reduced at high frequency in both non-small the tumor suppressor gene to a region containing BRG1 but lack- cell lung adenocarcinomas and squamous cell carcinomas (18). ing STK11 (32), thereby suggesting that selected cancers may arise These data provide compelling evidence for BRM loss as a contrib- from BRG1 mutations rather than aberrant STK11 function. Alter- utory factor in lung tumorigenesis. Similar observations were de- natively, BRG1 loss could occur as a secondary event in a subset of duced in examination of prostatic tissue, wherein loss of BRM has tumors that have deletions of the STK11 gene. Complementing been identified in multiple studies as associated with prostatic ad- these findings, studies in genetically engineered mice models enocarcinoma (38, 39), and additionally shown to correlate with
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