Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling
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Sirichat Kaowinn1, Jeonghyo Kim1, Jaebeom Lee1, Dong Hoon Shin2, Chi-Dug Kang3, Dae-Kee Kim4, Soojin Lee5, Min Kyung Kang6, Sang Seok Koh6, Seong-Jin Kim7, Young-Hwa Chung1
1BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea
2Department of Pathology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea
3Department of Biochemistry, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea
4Graduate School of Pharmaceutical Sciences, College of Pharmacy, EwhaWomans University, Seoul 120-750, Republic of Korea
5Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Republic of Korea
6Department of Biological Sciences, Dong-A University, Busan 604-714, Republic of Korea
7CHA Cancer Institute and Department of Biomedical Science, CHA University, Seoul 135-081, Republic of Korea
Young-Hwa Chung, email: [email protected]
Keywords: CUG2, TGF-β, EMT, Sp1, Smad2/3
Received: June 09, 2016 Accepted: November 22, 2016 Published: December 10, 2016
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.
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