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A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1

 Ji-Hyung Lee  ;  Su Myung Jung  ;  Kyung-Min Yang  ;  Eunjin Bae  ;  Sung Gwe Ahn  ;  Jin Seok Park  ;  Dongyeob Seo  ;  Minbeom Kim  ;  Jihoon Ha  ;  Jaewon Lee  ;  Jun-Hyeong Kim  ;  Jun Hwan Kim  ;  Akira Ooshima  ;  Jinah Park  ;  Donghyuk Shin  ;  Youn Sook Lee  ;  Sangho Lee  ;  Geert van Loo  ;  Joon Jeong  ;  Seong-Jin Kim  ;  Seok Hee Park 
 NATURE CELL BIOLOGY, Vol.19(10) : 1260-1273, 2017 
Journal Title
Issue Date
Animals ; Breast Neoplasms/drug therapy ; Breast Neoplasms/enzymology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Movement*/drug effects ; Drug Resistance, Neoplasm ; Epithelial-Mesenchymal Transition ; Female ; Gene Expression Regulation, Neoplastic ; Glycogen Synthase Kinase 3 beta/metabolism ; HEK293 Cells ; Humans ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Lung Neoplasms/prevention & control ; Lysine ; MCF-7 Cells ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, SCID ; Neoplastic Stem Cells/enzymology ; Neoplastic Stem Cells/pathology ; Phosphorylation ; Protein Stability ; RNA Interference ; Signal Transduction ; Snail Family Transcription Factors/genetics ; Snail Family Transcription Factors/metabolism ; Time Factors ; Transfection ; Transforming Growth Factor beta1/pharmacology ; Tumor Necrosis Factor alpha-Induced Protein 3/genetics ; Tumor Necrosis Factor alpha-Induced Protein 3/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; Ubiquitination*/drug effects
Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-β1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3β (GSK3β), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-β1-induced EMT and metastasis of basal-like breast cancers.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Ahn, Sung Gwe(안성귀) ORCID logo https://orcid.org/0000-0002-8778-9686
Jeong, Joon(정준) ORCID logo https://orcid.org/0000-0003-0397-0005
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