Oncotarget

Research Papers:

MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma

Lu-Kai Wang _, Szu-Hua Pan, Yih-Leong Chang, Pei-Fang Hung, Shih-Han Kao, Wen-Lung Wang, Ching-Wen Lin, Shuenn-Chen Yang, Chen-Hsien Liang, Chen-Tu Wu, Tzu-Hung Hsiao, Tse-Ming Hong and Pan-Chyr Yang

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Oncotarget. 2016; 7:386-401. https://doi.org/10.18632/oncotarget.6299

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Abstract

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

Correspondence to:

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

ABSTRACT

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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