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 KimSeok Hee Park

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1260-1273
Number of pages14
JournalNature Cell Biology
Volume19
Issue number10
DOIs
Publication statusPublished - 2017 Sep 29

Bibliographical note

Funding Information:
This work was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1520120) and in part by National Research Foundation grant of Korea (2015R1A2A2A05001344 and SRC 2017R1A5A1014560) funded by the Ministry of Science, ICR & Future Planning.

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Cell Biology

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