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

34 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

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Breast Neoplasms
Neoplasm Metastasis
Epithelial-Mesenchymal Transition
Lysine
Glycogen Synthase Kinase 3
Ubiquitin
Autoimmunity
Heterografts
Arginine
Phosphorylation
Inflammation
Lung
Mutation
Survival
Enzymes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Lee, J. H., Jung, S. M., Yang, K. M., Bae, E., Ahn, S. G., Park, J. S., ... 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
Lee, Ji Hyung ; Jung, Su Myung ; Yang, Kyung Min ; Bae, Eunjin ; Ahn, Sung Gwe ; Park, Jin Seok ; Seo, Dongyeob ; Kim, Minbeom ; Ha, Jihoon ; Lee, Jaewon ; Kim, Jun Hyeong ; Kim, Jun Hwan ; Ooshima, Akira ; Park, Jinah ; Shin, Donghyuk ; Lee, Youn Sook ; Lee, Sangho ; Van Loo, Geert ; Jeong, Joon ; Kim, Seong Jin ; Park, Seok Hee. / A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1. In: Nature Cell Biology. 2017 ; Vol. 19, No. 10. pp. 1260-1273.
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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.",
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Lee, JH, Jung, SM, Yang, KM, Bae, E, Ahn, SG, Park, JS, Seo, D, Kim, M, Ha, J, Lee, J, Kim, JH, Kim, JH, Ooshima, A, Park, J, Shin, D, Lee, YS, Lee, S, Van Loo, G, Jeong, J, Kim, SJ & Park, SH 2017, 'A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1', Nature Cell Biology, vol. 19, no. 10, pp. 1260-1273. https://doi.org/10.1038/ncb3609

A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1. / Lee, Ji Hyung; Jung, Su Myung; Yang, Kyung Min; Bae, Eunjin; Ahn, Sung Gwe; Park, Jin Seok; Seo, Dongyeob; Kim, Minbeom; Ha, Jihoon; Lee, Jaewon; Kim, Jun Hyeong; Kim, Jun Hwan; Ooshima, Akira; Park, Jinah; Shin, Donghyuk; Lee, Youn Sook; Lee, Sangho; Van Loo, Geert; Jeong, Joon; Kim, Seong Jin; Park, Seok Hee.

In: Nature Cell Biology, Vol. 19, No. 10, 29.09.2017, p. 1260-1273.

Research output: Contribution to journalArticle

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AU - Lee, Ji Hyung

AU - Jung, Su Myung

AU - Yang, Kyung Min

AU - Bae, Eunjin

AU - Ahn, Sung Gwe

AU - Park, Jin Seok

AU - Seo, Dongyeob

AU - Kim, Minbeom

AU - Ha, Jihoon

AU - Lee, Jaewon

AU - Kim, Jun Hyeong

AU - Kim, Jun Hwan

AU - Ooshima, Akira

AU - Park, Jinah

AU - Shin, Donghyuk

AU - Lee, Youn Sook

AU - Lee, Sangho

AU - Van Loo, Geert

AU - Jeong, Joon

AU - Kim, Seong Jin

AU - Park, Seok Hee

PY - 2017/9/29

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N2 - 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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