Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling.
Cancer upregulated gene 2 (CUG2) enhances cell migration and invasion, but the underlying mechanism has not been revealed. Herein, CUG2 decreased the expression of E-cadherin and increased the expression of N-cadherin and vimentin, characteristics of the epithelial-mesenchymal transition (EMT). A CUG2 deletion mutant, lacking interaction with nucleophosmin 1 (NPM1), or suppression of NPM1 reduced wound healing and cell invasion, indicating that CUG2-mediated EMT requires NPM1. CUG2 enhanced activation of Smad2/3 and expression of Snail and Twist, while the CUG2 silence decreased these TGF-β signaling pathways, leading to suppression of EMT. NPM silence also inhibited the CUG2-induced TGF-β signaling. These results suggest that TGF-β signaling is involved in CUG2-induced EMT. Treatment with EW-7197, a novel inhibitor of TGF-β signaling, diminished CUG2-mediated EMT and inhibition of Akt, ERK, JNK, and p38 MAPK, non-canonical TGF-β signaling molecules, also decreased expression of Smad2/3, Snail and Twist, leading to inhibition of EMT. The results confirm that TGF-β signaling is essential for CUG2-mediated EMT. Interestingly, TGF-β enhanced CUG2 expression. We further found that both CUG2-induced TGF-β production and TGF-β-induced CUG2 up-regulation required a physical interaction between Sp1 and Smad2/3 in the CUG2 and TGF-β promoter, as demonstrated by a promoter reporter assay, immunoprecipitation, and ChIP assay. These results indicated close crosstalk between CUG2 and TGF-β. Conversely, suppression of CUG2 or NPM1 did not completely inhibit TGF-β-induced EMT, indicating that the effect of TGF-β on EMT is dominant over the effect of CUG2 on EMT. Collectively, our findings suggest that CUG2 induces the EMT via TGF-β signaling.
['Kaowinn|Sirichat|S|', 'Kim|Jeonghyo|J|', 'Lee|Jaebeom|J|', 'Shin|Dong Hoon|DH|', 'Kang|Chi-Dug|CD|', 'Kim|Dae-Kee|DK|', 'Lee|Soojin|S|', 'Kang|Min Kyung|MK|', 'Koh|Sang Seok|SS|', 'Kim|Seong-Jin|SJ|', 'Chung|Young-Hwa|YH|']
D000072283:A549 Cells D015820:Cadherins D045744:Cell Line, Tumor D002868:Chromosomal Proteins, Non-Histone D058750:Epithelial-Mesenchymal Transition D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008175:Lung Neoplasms D000090243:Nucleophosmin D015398:Signal Transduction D016212:Transforming Growth Factor beta D014746:Vimentin
TGF-β CUG2 EMT Smad2/3 Sp1