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PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells
Guo, Weiwei1; You, Xue1,2; Xu, Daqian1; Zhang, Yuxue1; Wang, Zheng1; Man, Kaiyang1,2; Wang, Zhenzhen1; Chen, Yan1,2
Corresponding AuthorChen, Yan(ychen3@sibs.ac.cn)
2016-04-01
Source PublicationCARCINOGENESIS
ISSN0143-3334
Volume37Issue:4Pages:397-407
AbstractPAQR3, a tumor suppressor, can modulate ubiquitination and degradation of Twist1 that is a key factor for epithelial-mesenchymal transition of tumor cells. Twist1 is indispensable for the inhibitory effect of PAQR3 on metastasis of gastric cancer cells in mice.Twist1 is an essential transcription factor required to initiate epithelial-mesenchymal transition (EMT) and promote tumor metastasis. PAQR3 is a newly found tumor suppressor that is frequently downregulated in many types of human cancers. Downregulation of PAQR3 is associated with accelerated metastasis and poor prognosis of the patients with gastric cancers. In this study, we demonstrate that PAQR3 is actively involved in the degradation of Twist1 and whereby regulates EMT and metastasis of gastric cancer cells. PAQR3 overexpression reduces the protein level but not the mRNA level of Twist1. The protein stability and polyubiquitination of Twist1 are altered by PAQR3. PAQR3 forms a complex with Twist1 and BTRC, an E3 ubiquitin ligase. PAQR3 enhances the interaction between Twist1 and BTRC. Twist1 is mobilized from the nucleus to a proteasome-containing structure in the cytoplasm upon overexpression of PAQR3 and BTRC, which is required for PAQR3-induced degradation of Twist1. The Twist1 box domain of the Twist1 protein is required for the interaction of Twist1 with both PAQR3 and BTRC, indispensable for PAQR3-mediated degradation of Twist1. Both BTRC and Twist1 are required for the inhibitory effects of PAQR3 on migration and EMT phenotype of gastric cancers cells. Importantly, Twist1 is indispensable for the inhibitory effect of PAQR3 on metastasis of gastric cancer cells in vivo. Collectively, these findings not only pinpoint that Twist1 mediates the modulatory function of PAQR3 on EMT and metastasis but also suggest that targeting Twist1 is a promising strategy to control metastasis of tumors with downregulation of PAQR3.
Funding OrganizationNational Natural Science Foundation of China ; Ministry of Science and Technology of China
DOI10.1093/carcin/bgw013
Indexed BySCI
Language英语
Funding ProjectNational Natural Science Foundation of China[81390350] ; National Natural Science Foundation of China[81130077] ; National Natural Science Foundation of China[81321062] ; Ministry of Science and Technology of China[2012CB524900] ; Ministry of Science and Technology of China[2013BAI04B03]
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000374245300006
PublisherOXFORD UNIV PRESS
Citation statistics
Cited Times:23[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.imr.ac.cn/handle/321006/121982
Collection中国科学院金属研究所
Corresponding AuthorChen, Yan
Affiliation1.Chinese Acad Sci, Grad Sch Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Nutr & Metab,Inst Nutr Sci, 320 Yueyang Rd,New Life Sci Bldg,A2214, Shanghai 200031, Peoples R China
2.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
Recommended Citation
GB/T 7714
Guo, Weiwei,You, Xue,Xu, Daqian,et al. PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells[J]. CARCINOGENESIS,2016,37(4):397-407.
APA Guo, Weiwei.,You, Xue.,Xu, Daqian.,Zhang, Yuxue.,Wang, Zheng.,...&Chen, Yan.(2016).PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells.CARCINOGENESIS,37(4),397-407.
MLA Guo, Weiwei,et al."PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells".CARCINOGENESIS 37.4(2016):397-407.
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