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 journalArticle

41 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

All Science Journal Classification (ASJC) codes

  • Cell Biology

Fingerprint Dive into the research topics of 'A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1'. Together they form a unique fingerprint.

  • Cite this

    Lee, J. H., Jung, S. M., Yang, K. M., Bae, E., Ahn, S. G., Park, J. S., Seo, D., Kim, M., Ha, J., Lee, J., Kim, J. H., Kim, J. H., Ooshima, A., Park, J., Shin, D., Lee, Y. S., Lee, S., Van Loo, G., Jeong, J., ... Park, S. H. (2017). A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1. Nature Cell Biology, 19(10), 1260-1273. https://doi.org/10.1038/ncb3609