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

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...

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Detalles Bibliográficos
Autores principales: 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, Shi, Qiuying, Deng, Jiong, Mark Evers, B, Zhou, Binhua P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316870/
https://www.ncbi.nlm.nih.gov/pubmed/28198361
http://dx.doi.org/10.1038/ncomms14228
Descripción
Sumario: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.

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