Faculty Collaboration Database

Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation. Nat Commun 2017 Feb 15;8:14228

Date

02/16/2017

Pubmed ID

28198361

Pubmed Central ID

PMC5316870

DOI

10.1038/ncomms14228

Scopus ID

2-s2.0-85012981912 (requires institutional sign-in at Scopus site)   114 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.

Author List

Wu Y, Wang Y, Lin Y, Liu Y, Wang Y, Jia J, Singh P, Chi YI, Wang C, Dong C, Li W, Tao M, Napier D, Shi Q, Deng J, Evers BM, Zhou BP

Author

Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Breast Neoplasms
Cell Line, Tumor
Cell Movement
Down-Regulation
Endopeptidases
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
HEK293 Cells
Humans
Interleukin-6
Mice, SCID
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplastic Stem Cells
Protein Binding
Protein Stability
Protein Transport
Proteolysis
Snail Family Transcription Factors
Ubiquitination