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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, D Nature Publishing Group 2017 NATURE CELL BIOLOGY Vol. No.
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.
Kwak, Mi-Kyung,Yang, Kyung-Min,Park, Jinah,Lee, Siyoung,Park, Yuna,Hong, Eunji,Sun, Eun Jin,An, Haein,Park, Sujin,Pang, Kyoungwha,Lee, Jihee,Kang, Jin Muk,Kim, Pyunggang,Ooshima, Akira,Kim, Seong-Jin Elsevier 2017 Biochemical and biophysical research communication Vol. No.
<P><B>Abstract</B></P> <P>Smad3 linker phosphorylation is a candidate target for several kinases that play important roles in cancer cell initiation, proliferation and progression. Also, Smad3 is an essential intracellular mediator of TGF-β1-induced transcriptional responses during carcinogenesis. Therefore, it is highly advantageous to identify and develop inhibitors targeting Smad3 linker phosphorylation for the treatment of cancers. Galangin (3,5,7-trihydroxyflavone) has been known to be an active flavonoid showing a cytotoxic effect on several cancer cells. However, the mechanism of action of galangin in various cancers remains unclear, and there has been no report concerning regulation of Smad3 phosphorylation by galangin. In the present study, we show that galangin significantly induced apoptosis and inhibited cell proliferation in the presence of TGF-β1 in both human prostate and pancreatic cancer cell lines. Particularly, galangin effectively inhibits phosphorylation of the Thr-179 site at Smad3 linker region through suppression of CDK4 phosphorylation. Thus, galangin can be a promising candidate as a selective inhibitor to suppress phosphorylation of Smad3 linker region.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Galangin significantly induced apoptosis in the presence of TGF-β1. </LI> <LI> Galangin inhibits phosphorylation of the Thr-179 site at the Smad3 linker region. </LI> <LI> Galangin suppresses CDK4-mediated Smad3 linker phosphorylation. </LI> </UL> </P>