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

doi:10.1038/ncomms14228

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

Hormel Institute

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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 language	English (US)
Article number	14228
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14228
State	Published - Feb 15 2017

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© The Author(s) 2017.

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title = "Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation",

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.",

author = "Yadi Wu and Yu Wang and Yiwei Lin and Yajuan Liu and Yifan Wang and Jianhang Jia and Puja Singh and Chi, {Young In} and Chi Wang and Chenfang Dong and Wei Li and Min Tao and Dana Napier and Qiuying Shi and Jiong Deng and {Mark Evers}, B. and Zhou, {Binhua P.}",

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doi = "10.1038/ncomms14228",

language = "English (US)",

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AU - Wu, Yadi

AU - Wang, Yu

AU - Lin, Yiwei

AU - Liu, Yajuan

AU - Wang, Yifan

AU - Jia, Jianhang

AU - Singh, Puja

AU - Chi, Young In

AU - Wang, Chi

AU - Dong, Chenfang

AU - Li, Wei

AU - Tao, Min

AU - Napier, Dana

AU - Shi, Qiuying

AU - Deng, Jiong

AU - Mark Evers, B.

AU - Zhou, Binhua P.

PY - 2017/2/15

Y1 - 2017/2/15

N2 - 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.

AB - 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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VL - 8

JO - Nature communications

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

Abstract

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