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, Binhua P. Zhou

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Article number14228
JournalNature communications
Volume8
DOIs
StatePublished - Feb 15 2017

Bibliographical note

Funding Information:
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).

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