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.
authors.affiliation: Department of Pharmacology &Nutritional Sciences, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Yadi
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Pharmacology &Nutritional Sciences, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Yiwei
authors.identifier: 0000-0003-1503-9082
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Jianhang
authors.initials: J
authors.lastname: Jia
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Puja
authors.initials: P
authors.lastname: Singh
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Chi
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Biostatistics, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Zhejiang 310058, China.
authors.forename: Chenfang
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou 215006, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, PREMED Key Laboratory for Precision Medicine, Soochow University, Suzhou 215006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Tao
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Pathology, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Napier
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Pathology, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Minister of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Deng
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Surgery, the University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.affiliation: Markey Cancer Center, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|Department of Molecular and Cellular Biochemistry, The University of Kentucky, College of Medicine, Lexington, Kentucky 40506, USA.|State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
authors.forename: Binhua P
authors.initials: BP
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D059748:Proteolysis; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D015850:Interleukin-6; D000071250:Snail Family Transcription Factors; D010450:Endopeptidases; C484854:USP17L2 protein, human