SND1 Acts Downstream of TGF 1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis

L. Yu, X. Liu, K. Cui, Y. Di, L. Xin, X. Sun, W. Zhang, X. Yang, M. Wei, Z. Yao, J. Yang
2015 Cancer Research  
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 TGFb1 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 the SND1 gene was controlled by the TGFb1/Smad pathway, specifically by
more » ... ation of the Smad2/Smad3 complex. The SND1 promoter region contained several Smad-spe-cific 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. Ó2015 AACR. Materials and Methods Cell lines, siRNA, and cell transfection The cell lines MCF-7, T47D, SK-BR-3, MDA-MB-231, and BT549 were obtained from the ATCC. MDA-MB-231 was
doi:10.1158/0008-5472.can-14-2387 pmid:25596283 fatcat:bagip76h6zc3tbwkuilflqxloq