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

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.

• Authors: 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
• Journal: Nature cell biology (Nat Cell Biol) Vol. 19 Issue 10 Pg. 1260-1273 (Oct 2017) ISSN: 1476-4679 [Electronic] England
• PMID: 28892081 (Publication Type: Journal Article)

Chemical References

• SNAI1 protein, human
• Snai1 protein, mouse
• Snail Family Transcription Factors
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• TNFAIP3 protein, human
• Tumor Necrosis Factor alpha-Induced Protein 3
• Tnfaip3 protein, mouse
• Lysine

Topics

• Animals
• Breast Neoplasms (drug therapy, enzymology, genetics, 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, genetics, pathology, prevention & control)
• Lysine
• MCF-7 Cells
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, SCID
• Neoplastic Stem Cells (enzymology, pathology)
• Phosphorylation
• Protein Stability
• RNA Interference
• Signal Transduction
• Snail Family Transcription Factors (genetics, metabolism)
• Time Factors
• Transfection
• Transforming Growth Factor beta1 (pharmacology)
• Tumor Necrosis Factor alpha-Induced Protein 3 (genetics, metabolism)
• Tumor Necrosis Factor-alpha (pharmacology)
• Ubiquitination (drug effects)