SND1 Acts Downstream of TGF beta 1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis
SND1 Acts Downstream of TGF beta 1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis
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SND1 作用于 TGF beta 1 下游和 Smurf1 上游，促进乳腺癌转移
DOI：
10.1158/0008-5472.can-14-2387
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发表时间：
2015
期刊：
影响因子：
11.2
通讯作者：
Yang Jie
中科院分区：
文献类型：
--
作者：
Yu Lin;Liu Xin;Cui Kang;Di Yanbo;Xin Lingbiao;Sun Xiaoming;Zhang Wei;Yang Xi;Wei Minxin;Yao Zhi;Yang Jie
SND 1是一种AEG-1/MTDH/LYRIC结合蛋白，在许多人类癌症中上调，其中它被赋予多种功能作用。在这项研究中，我们报告了它与TGFβ1信号通路的关系，该信号通路促进乳腺癌中的上皮-间质转化（EMT）。SND 1在乳腺癌组织中上调，特别是在原发性浸润性导管癌中。SND 1基因的转录激活受TGFβ1/Smad通路控制，特别是受Smad 2/Smad 3复合物的激活控制。SND 1启动子区域包含几个Smad特异性识别结构域（RD基序），这些结构域被Smad复合物识别并结合，从而增强SND 1的转录激活。我们发现SND 1促进E3泛素连接酶Smurf 1的表达，导致RhoA泛素化和降解。RhoA在乳腺癌细胞中的降解破坏了F-肌动蛋白细胞骨架组织，降低了细胞粘附，增加了细胞迁移和侵袭，并促进了转移。总的来说，我们的研究结果确定了SND 1在调节乳腺肿瘤发生和转移中的新作用。©2015 AACR.
SND1 is an AEG-1/MTDH/LYRIC-binding protein that is upregulated in numerous human cancers, where it has been assigned multiple functional roles. In this study, we report its association with the TGFβ1 signaling pathway, which promotes epithelial–mesenchymal transition (EMT) in breast cancer. SND1 was upregulated in breast cancer tissues, in particular in primary invasive ductal carcinomas. Transcriptional activation of theSND1gene was controlled by the TGFβ1/Smad pathway, specifically by activation of the Smad2/Smad3 complex. TheSND1promoter region contained several Smad-specific recognition domains (RD motifs), which were recognized and bound by the Smad complex that enhanced the transcriptional activation of SND1. We found that SND1 promoted expression of the E3 ubiquitin ligase Smurf1, leading to RhoA ubiquitination and degradation. RhoA degradation in breast cancer cells disrupted F-actin cytoskeletal organization, reduced cell adhesion, increased cell migration and invasion, and promoted metastasis. Overall, our results define a novel role for SND1 in regulating breast tumorigenesis and metastasis.Cancer Res; 75(7); 1275–86. ©2015 AACR.