Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness

Abstract

BackgroundMetastatic melanoma is an aggressive malignancy that is resistant to therapy and has a poor prognosis. The progression of primary melanoma to metastatic disease is a multi-step process that requires dynamic regulation of gene expression through currently uncharacterized epigenetic mechanisms. Epigenetic regulation of gene expression often involves changes in chromatin structure that are catalyzed by chromatin remodeling enzymes. Understanding the mechanisms involved in the regulation of gene expression during metastasis is important for developing an effective strategy to treat metastatic melanoma. SWI/SNF enzymes are multisubunit complexes that contain either BRG1 or BRM as the catalytic subunit. We previously demonstrated that heterogeneous SWI/SNF complexes containing either BRG1 or BRM are epigenetic modulators that regulate important aspects of the melanoma phenotype and are required for melanoma tumorigenicity in vitro.ResultsTo characterize BRG1 expression during melanoma progression, we assayed expression of BRG1 in patient derived normal skin and in melanoma specimen. BRG1 mRNA levels were significantly higher in stage IV melanomas compared to stage III tumors and to normal skin. To determine the role of BRG1 in regulating the expression of genes involved in melanoma metastasis, we expressed BRG1 in a melanoma cell line that lacks BRG1 expression and examined changes in extracellular matrix and adhesion molecule expression. We found that BRG1 modulated the expression of a subset of extracellular matrix remodeling enzymes and adhesion proteins. Furthermore, BRG1 altered melanoma adhesion to different extracellular matrix components. Expression of BRG1 in melanoma cells that lack BRG1 increased invasive ability while down-regulation of BRG1 inhibited invasive ability in vitro. Activation of metalloproteinase (MMP) 2 expression greatly contributed to the BRG1 induced increase in melanoma invasiveness. We found that BRG1 is recruited to the MMP2 promoter and directly activates expression of this metastasis associated gene.ConclusionsWe provide evidence that BRG1 expression increases during melanoma progression. Our study has identified BRG1 target genes that play an important role in melanoma metastasis and we show that BRG1 promotes melanoma invasive ability in vitro. These results suggest that increased BRG1 levels promote the epigenetic changes in gene expression required for melanoma metastasis to proceed.

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

“…Taken together, these results suggest that SMARCA4 positively regulates genes associated with ECM, supporting the role for SMARCA4 in ECM biology (Xu et al 2007;Stankunas et al 2008;Saladi et al 2010), and negatively regulates genes related to lipid metabolism and calcium signaling in mammary epithelial cells. Moreover, SMARCA4 also regulates the expression of many lncRNAs.…”

DNA and Chromatin Modification Networks Distinguish Stem Cell Pluripotent Ground States

“…Expression of Smarcd1/Baf60a and Smarca4/Brg1 were both significantly higher in mEpiSCs than mESCs. Interestingly, Smarcd1/Baf60a mediates the interaction between several signaling pathways and BAF complexes (40). In human cells, a direct interaction between p53 with SMARCD1/BAF60A (but not between p53 and SMARCA4/BRG1) has been reported (41).…”

SWI/SNF Chromatin Remodeling Enzymes in Melanocyte Differentiation and Melanoma

“…36 Yet another study indicated that BRG1 messenger RNA levels were significantly higher in stage IV melanoma samples compared to normal and stage III melanoma samples. 60 Interestingly, recent exome sequencing studies have detected BRG1 mutations at a low frequency in patient-derived melanoma samples 53 (Table 1). These studies suggest that BRG1 function may be compromised in a small subset of melanomas.…”

“…24,46 The requirement for SWI/SNF activity is associated with MITF-dependent and -independent functions. 24,36,46,47,60 …”