Dataset Information

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

ABSTRACT:

Background

Metastatic 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.

Results

To 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.

Conclusions

We 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.

SUBMITTER: Saladi SV

PROVIDER: S-EPMC3098014 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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

Saladi Srinivas Vinod SV Keenen Bridget B Marathe Himangi G HG Qi Huiling H Chin Khew-Voon KV de la Serna Ivana L IL

Molecular cancer 20101022

<h4>Background</h4>Metastatic 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 reg ...[more]

PMID: 20969766

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Project description:The production of fibrosis in response to chronic alcohol abuse is well recognized in liver but has not been fully characterized in striated muscle and may contribute to functional impairment. Therefore, the purpose of this study was to use an unbiased discovery-based approach to determine the effect of chronic alcohol consumption on the expression profile of genes important for cell-cell and cell-extracellular matrix (ECM) interactions in both skeletal and cardiac muscle.Adult male rats were pair-fed an alcohol-containing liquid diet or control diet for 24 weeks, and skeletal muscle (gastrocnemius) and heart were collected in the freely fed state. A pathway-focused gene expression polymerase chain reaction array was performed on these tissues to assess mRNA content for 84 ECM proteins, and selected proteins were confirmed by Western blot analysis.In gastrocnemius, alcohol feeding up-regulated the expression of 11 genes and down-regulated the expression of 1 gene. Alcohol increased fibrosis as indicated by increased mRNA and/or protein for collagens ?1(I), ?2(I), ?1(III), and ?2(IV) as well as hydroxyproline. Alcohol also increased ?-smooth muscle actin protein, an index of myofibroblast activation, but no concomitant change in transforming growth factor-? was detected. The mRNA and protein content for other ECM components, such as integrin-?5, L-selectin, PECAM, SPARC, and ADAMTS2, were also increased by alcohol. Only laminin-?3 mRNA was decreased in gastrocnemius from alcohol-fed rats, while 66 ECM- or cell adhesion-related mRNAs were unchanged by alcohol. For heart, expression of 16 genes was up-regulated, expression of 3 genes was down-regulated, and 65 mRNAs were unchanged by alcohol; there were no common alcohol-induced gene expression changes between heart and skeletal muscle. Finally, alcohol increased tumor necrosis factor-? and interleukin (IL)-12 mRNA in both skeletal and cardiac muscle, but IL-6 mRNA was increased and IL-10 mRNA decreased only in skeletal muscle.These data demonstrate a fibrotic response in striated muscle from chronic alcohol-fed rats which is tissue specific in nature, suggesting different regulatory mechanisms.

Dataset Information

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

Background

Results

Conclusions

Publications

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

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