title: Cancer upregulated gene 2 induces epithelial-mesenchymal transition of human lung cancer cells via TGF-β signaling.
abstract: 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.
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Sirichat
authors.initials: S
authors.lastname: Kaowinn
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jeonghyo
authors.initials: J
authors.lastname: Kim
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jaebeom
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, EwhaWomans University, Seoul 120-750, Republic of Korea.
authors.forename: Dae-Kee
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Soojin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Dong-A University, Busan 604-714, Republic of Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Kang
authors.affiliation: Department of Biological Sciences, Dong-A University, Busan 604-714, Republic of Korea.
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
authors.affiliation: CHA Cancer Institute and Department of Biomedical Science, CHA University, Seoul 135-081, Republic of Korea.
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
mesh_terms: D000072283:A549 Cells; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism
chemical_list: C534000:CENPW protein, human; D015820:Cadherins; D002868:Chromosomal Proteins, Non-Histone; C000716967:NPM1 protein, human; D016212:Transforming Growth Factor beta; D014746:Vimentin; D000090243:Nucleophosmin
keywords: CUG2; EMT; Smad2/3; Sp1; TGF-β