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 vitroand in vivo. Our study reveals a critical Dub3–Snail1 signalling axis in EMT and metastasis, and provides an effective therapeutic approach against breast cancer.
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This research was supported by the Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558 to B.M.E.). This work was also supported by grants from NIH (CA125454 and CA188118), DoD (BC140733P1), Mary Kay Ash Foundation and the Frankfort Country Club's Ladies Golf Association (to B.P. Zhou), and American Cancer Society Research Scholar Award (RSG13187) (to Y.Wu).
Supplementary Information accompanies this paper at http://www.nature.com/naturecommunications
Wu, Yadi; Wang, Yu; Lin, Yiwei; Liu, Yajuan; Wang, Yifan; Jia, Jianhang; Singh, Puja; Chi, Young-In; Wang, Chi; Dong, Chenfang; Li, Wei; Tao, Min; Napier, Dana L.; Shi, Qiuying; Deng, Jiong; Evers, B. Mark; and Zhou, Binhua P., "Dub3 Inhibition Suppresses Breast Cancer Invasion and Metastasis by Promoting Snail1 Degradation" (2017). Pharmacology and Nutritional Sciences Faculty Publications. 52.