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.

中文翻译：

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A20通过Snail1的多单泛素化促进侵袭性基底样乳腺癌的转移。

尽管泛素编辑酶A20是炎症和自身免疫的关键因素，但其在癌症转移中的作用仍然未知。在这里，我们显示A20在三个赖氨酸残基上单核苷酸泛素化Snail1，从而促进侵袭性基底样乳腺癌的转移。A20在人基底样乳腺癌中显着上调，其表达水平与无转移的患者生存率呈负相关。A20通过Snail1的多单泛素化促进TGF-β1诱导的乳腺癌细胞上皮-间质转化（EMT）。单泛素化的Snail1对糖原合酶激酶3β（GSK3β）的亲和力降低，因此通过减少的磷酸化作用而稳定在细胞核中。小鼠异种移植和原位乳腺癌模型中，A20的敲低或Snail1的过表达以及单泛素化的赖氨酸残基突变为精氨酸消除了肺转移，这表明A20和单泛素化的Snail1是转移所必需的。我们的发现揭示了A20-Snail1轴在TGF-β1诱导的EMT和基底样乳腺癌转移中的重要作用。