MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma
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Lu-Kai Wang1, Szu-Hua Pan2,3, Yih-Leong Chang4, Pei-Fang Hung1, Shih-Han Kao6, Wen-Lung Wang7, Ching-Wen Lin8, Shuenn-Chen Yang8, Chen-Hsien Liang9, Chen-Tu Wu4, Tzu-Hung Hsiao10, Tse-Ming Hong11,12,*, Pan-Chyr Yang1,5,8,*
1Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
2Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
3Doctoral Degree Program of Translational Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
4Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
5NTU Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
6Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan
7Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
8Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
9Division of Isotope application, Institute of Nuclear Energy Research, Taoyuan, Taiwan
10Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
11Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
12Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan
*These authors have contributed equally to this work
Pan-Chyr Yang, e-mail: [email protected]
Tse-Ming Hong, e-mail: [email protected]
Keywords: Syntenin, Slug, EMT, invasion, lung adenocarcinoma
Received: August 05, 2015 Accepted: October 20, 2015 Published: November 02, 2015
Melanoma differentiation-associated gene-9 (MDA-9)/Syntenin is a novel therapeutic target because it plays critical roles in cancer progression and exosome biogenesis. Here we show that Slug, a key epithelial-mesenchymal-transition (EMT) regulator, is a MDA-9/Syntenin downstream target. Mitogen EGF stimulation increases Slug expression and MDA-9/Syntenin nuclear translocation. MDA-9/Syntenin uses its PDZ1 domain to bind with Slug, and this interaction further leads to HDAC1 recruitment, up-regulation of Slug transcriptional repressor activity, enhanced Slug-mediated EMT, and promotion of cancer invasion and metastasis. The PDZ domains and nuclear localization of MDA-9/Syntenin are both required for promoting Slug-mediated cancer invasion. Clinically, patients with high MDA-9/Syntenin and high Slug expressions were associated with poor overall survival compared to those with low expression in lung adenocarcinomas. Our findings provide evidence that MDA-9/Syntenin acts as a pivotal adaptor of Slug and it transcriptionally enhances Slug-mediated EMT to promote cancer invasion and metastasis.
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