Stabilization of the transcription factors slug and twist by the deubiquitinase dub3 is a key requirement for tumor metastasis
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Yiwei Lin1,4,*, Yu Wang2,4,*, Qing Shi1,4, Qian Yu2,4, Cuicui Liu1,4,5, Jing Feng5, Jiong Deng6, B. Mark Evers3,4, Binhua P. Zhou1,4 and Yadi Wu2,4
1Department of Molecular and Cellular Biochemistry, Lexington, KY, USA
2Department of Pharmacology & Nutritional Sciences, Lexington, KY, USA
3Department of Surgery, Lexington, KY, USA
4Markey Cancer Center, the University of Kentucky, College of Medicine, Lexington, KY, USA
5Department of Laboratory Medicine & Central Laboratory, Shanghai Fengxian District Central Hospital, Shanghai, China
6Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
*Authors contributed equally to this work
Binhua P. Zhou, email: [email protected]
Yadi Wu, email: [email protected]
Keywords: Dub3, Slug, Twist, IL-6, metastasis
Received: July 18, 2017 Accepted: August 09, 2017 Published: August 24, 2017
The Epithelial-mesenchymal transition (EMT) represents a cellular de-differentiation process that provides cells with the increased plasticity required during embryonic development, tissue remodeling, wound healing and metastasis. Slug and Twist are two key EMT transcription factors (EMT-TFs) that are tightly regulated via ubiquitination and degradation. How Slug and Twist escape degradation and become stabilized in cancer cells remains unclear. One plausible mechanism of Slug and Twist stabilization involves removal of ubiquitin by deubiquitinases (DUBs). In this study, we identified Dub3 as a novel DUB for both Slug and Twist. We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose-dependent manner, whereas Dub3-knockdown decreased their protein levels. Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells. Intriguingly, Dub3 was identified as an early response gene that was upregulated after exposure to inflammatory cytokines such as IL-6, which plays a critical role in the growth and metastasis of breast cancer cells, as well as the maintenance of breast CSCs. We found that Dub3 played an essential role in IL-6 induced EMT through stabilization of Slug and Twist. Our study has uncovered an IL-6-Dub3-Slug/Twist signaling axis during EMT and suggests potential approaches that could target Dub3 to prevent metastatic breast tumor.
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