β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling
β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling
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DOI：
10.1038/onc.2012.527
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发表时间：
2013-10-17
期刊：
影响因子：
8
通讯作者：
Bagnato, A.
中科院分区：
文献类型：
--
作者：
Rosano, L.;Cianfrocca, R.;Bagnato, A.
尽管β-连环蛋白在肿瘤进展中具有重要的病理生理学意义，但其最终转录产物的机制已部分阐明。在这里，我们报告说，β-arrestin-1（β-arr 1）是内皮素（ET）-1诱导的β-连环蛋白信号在上皮性卵巢癌（EOC）的表观遗传调节。作为对ET-1激活ET A受体（ETAR）的响应，beta-arr 1增加了其核移位并与β-连环蛋白的直接结合。这反过来又增强了β-连环蛋白的核积累和转录活性，这是通过表达一种不能核分布的突变体β-arr 1来阻止的。β-arr 1-β-连环蛋白相互作用通过促进组蛋白去乙酰化酶1（HDAC 1）解离和p300乙酰转移酶在这些启动子基因上的募集来控制β-连环蛋白靶基因表达，如ET-1、Axin 2、基质金属蛋白酶2和细胞周期蛋白D1，导致细胞迁移所需的H3和H4组蛋白乙酰化和基因转录增强，侵袭和上皮向间充质转化。这些作用被beta-arr 1沉默或突变体beta-arr 1以及beta-catenin或p300沉默所消除，证实了核beta-arr 1形成能够调节beta-catenin驱动的侵入行为中的表观遗传变化的功能复合物。在转移性人EOC的鼠原位模型中，沉默β-arr 1或突变型β-arr 1表达以及ETAR阻断可抑制转移。在人EOC组织中，β-arr 1-β-连环蛋白核复合物在β-连环蛋白靶基因启动子处选择性富集，与肿瘤分级相关，证实了在参与EOC进展的特定基因组处的直接体内β-arr 1-β-连环蛋白关联。总的来说，我们的研究提供了关于β-arr 1介导的表观遗传机制如何控制β-连环蛋白活性的见解，揭示了其促进转移的核功能所需的新成分。
Despite the fundamental pathophysiological importance of beta-catenin in tumor progression, the mechanism underlying its final transcriptional output has been partially elucidated. Here, we report that beta-arrestin-1 (beta-arr1) is an epigenetic regulator of endothelin (ET)-1-induced beta-catenin signaling in epithelial ovarian cancer (EOC). In response to ET A receptor (ETAR) activation by ET-1, beta-arr1 increases its nuclear translocation and direct binding to beta-catenin. This in turn enhanced beta-catenin nuclear accumulation and transcriptional activity, which was prevented by expressing a mutant beta-arr1 incapable of nuclear distribution. beta-arr1-beta-catenin interaction controls beta-catenin target gene expressions, such as ET-1, Axin 2, Matrix metalloproteinase 2, and Cyclin D1, by promoting histone deacetylase 1 (HDAC1) dissociation and the recruitment of p300 acetyltransferase on these promoter genes, resulting in enhanced H3 and H4 histone acetylation, and gene transcription, required for cell migration, invasion and epithelial-to-mesenchymal transition. These effects are abrogated by beta-arr1 silencing or by mutant beta-arr1, as well as by beta-catenin or p300 silencing, confirming that nuclear beta-arr1 forms a functional complex capable of regulating epigenetic changes in beta-catenin-driven invasive behavior. In a murine orthotopic model of metastatic human EOC, silencing of beta-arr1 or mutant beta-arr1 expression, as well as ETAR blockade, inhibits metastasis. In human EOC tissues, beta-arr1-beta-catenin nuclear complexes are selectively enriched at beta-catenin target gene promoters, correlating with tumor grade, confirming a direct in vivo beta-arr1-beta-catenin association at specific set of genes involved in EOC progression. Collectively, our study provides insights into how a beta-arr1-mediated epigenetic mechanism controls beta-catenin activity, unraveling new components required for its nuclear function in promoting metastasis.