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