Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling

Sirichat Kaowinn, Jeonghyo Kim, Jaebeom Lee, Dong Hoon Shin, Chi Dug Kang, Dae Kee Kim, Soojin Lee, Min Kyung Kang, Sang Seok Koh, Seong Jin Kim, Young Hwa Chung

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish
Pages (from-to)5092-5110
Number of pages19
Issue number3
StatePublished - 2017

Bibliographical note

Funding Information:
We are grateful to Charles C. Chung and Michael Murray for proofreading this manuscript. This study was supported by a grant from the Basic Research Program of the National Research Foundation, funded by the Korean government (NRF-2014R A1A2053750).


  • CUG2
  • EMT
  • Smad2/3
  • Sp1
  • TGF-β


Dive into the research topics of 'Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling'. Together they form a unique fingerprint.

Cite this