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

Research output: Contribution to journal › Article › peer-review

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

Bibliographical note

Publisher Copyright:
© The Author(s) 2017.

Funding

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).

Funders	Funder number
Frankfort Country Club's Ladies Golf Association
National Institutes of Health (NIH)	CA125454
U.S. Department of Defense	BC140733P1
American Cancer Society-Michigan Cancer Research Fund	RSG13187
National Childhood Cancer Registry – National Cancer Institute	R01CA188118
Mary Kay Ash Foundation
University of Kentucky Markey Comprehensive Cancer Center	P30CA177558

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/ncomms14228

Cite this

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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.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

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doi = "10.1038/ncomms14228",

language = "English",

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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

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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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UR - https://www.scopus.com/pages/publications/85012981912#tab=citedBy

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DO - 10.1038/ncomms14228

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

M1 - 14228

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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