Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness.
Modulation of extracellular matrix/adhesion molecule expression by BRG1 is associated with increased melanoma invasiveness.
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DOI：
10.1186/1476-4598-9-280
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发表时间：
2010-10-22
期刊：
影响因子：
37.3
通讯作者：
de la Serna IL
中科院分区：
文献类型：
--
作者：
Saladi SV;Keenen B;Marathe HG;Qi H;Chin KV;de la Serna IL
转移性黑色素瘤是一种侵袭性恶性肿瘤，对治疗有抵抗力，预后差。原发性黑色素瘤向转移性疾病的进展是一个多步骤的过程，需要通过目前尚未表征的表观遗传机制动态调节基因表达。基因表达的表观遗传调控通常涉及染色质结构的改变，这是由染色质重塑酶催化的。了解转移过程中基因表达调控的机制对于制定治疗转移性黑色素瘤的有效策略至关重要。SWI/SNF酶是含有BRG1或BRM作为催化亚基的多亚基复合物。我们之前证明含有BRG1或BRM的异质SWI/SNF复合物是调控黑色素瘤表型重要方面的表观遗传调节剂，并且是体外黑色素瘤致瘤性所必需的。为了表征BRG1在黑色素瘤进展过程中的表达，我们检测了BRG1在患者来源的正常皮肤和黑色素瘤标本中的表达。与III期肿瘤和正常皮肤相比，IV期黑色素瘤中BRG1 mRNA水平显著升高。为了确定BRG1在调节黑色素瘤转移相关基因表达中的作用，我们在缺乏BRG1表达的黑色素瘤细胞系中表达BRG1，并检测细胞外基质和粘附分子表达的变化。我们发现BRG1调节细胞外基质重塑酶和粘附蛋白的表达。此外，BRG1改变了黑色素瘤对不同细胞外基质成分的粘附。在体外实验中，缺乏BRG1的黑色素瘤细胞中BRG1的表达增加了侵袭能力，而BRG1的下调则抑制了侵袭能力。金属蛋白酶（MMP） 2表达的激活在很大程度上促进了BRG1诱导的黑色素瘤侵袭性的增加。我们发现BRG1被募集到MMP2启动子并直接激活该转移相关基因的表达。我们提供的证据表明，BRG1表达在黑色素瘤进展过程中增加。我们的研究已经确定了BRG1靶基因在黑色素瘤转移中发挥重要作用，我们表明BRG1在体外促进黑色素瘤的侵袭能力。这些结果表明，BRG1水平的升高促进了黑色素瘤转移进行所需的基因表达的表观遗传变化。
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. 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. 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.
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影响因子：
11.2
作者：
Banine, F;Bartlett, C;Sherman, LS
通讯作者：
Sherman, LS
影响因子：
6.5
作者：
Hofmann, UB;Westphal, JR;Ruiter, DJ
通讯作者：
Ruiter, DJ
影响因子：
8
作者：
Doan, DN;Veal, TM;Imbalzano, AN
通讯作者：
Imbalzano, AN
影响因子：
5.3
作者：
De la Serna, IL;Carlson, KA;Imbalzano, AN
通讯作者：
Imbalzano, AN
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影响因子：
4.8
作者：
Huntington, JT;Shields, JM;Brinckerhoff, CE
通讯作者：
Brinckerhoff, CE