Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation

Yadi Wu (), Yu Wang, Yiwei Lin, Yajuan Liu, Yifan Wang, Jianhang Jia, Puja Singh, Young-In Chi, Chi Wang, Chenfang Dong, Wei Li, Min Tao, Dana Napier, Qiuying Shi, Jiong Deng, B Mark Evers and Binhua P. Zhou ()
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Yadi Wu: The University of Kentucky, College of Medicine
Yu Wang: The University of Kentucky, College of Medicine
Yiwei Lin: Markey Cancer Center, The University of Kentucky, College of Medicine
Yajuan Liu: Markey Cancer Center, The University of Kentucky, College of Medicine
Yifan Wang: Markey Cancer Center, The University of Kentucky, College of Medicine
Jianhang Jia: Markey Cancer Center, The University of Kentucky, College of Medicine
Puja Singh: The Hormel Institute, University of Minnesota
Young-In Chi: The Hormel Institute, University of Minnesota
Chi Wang: Markey Cancer Center, The University of Kentucky, College of Medicine
Chenfang Dong: Zhejiang University School of Medicine
Wei Li: The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University
Min Tao: The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University
Dana Napier: Markey Cancer Center, The University of Kentucky, College of Medicine
Qiuying Shi: Markey Cancer Center, The University of Kentucky, College of Medicine
Jiong Deng: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine
B Mark Evers: Markey Cancer Center, The University of Kentucky, College of Medicine
Binhua P. Zhou: Markey Cancer Center, The University of Kentucky, College of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitro and in vivo. Our study reveals a critical Dub3–Snail1 signalling axis in EMT and metastasis, and provides an effective therapeutic approach against breast cancer.

Date: 2017
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DOI: 10.1038/ncomms14228

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