title: PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells.
abstract: 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.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences , 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031 , China and.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031, China and.|School of Life Sciences and Technology, Shanghai Tech University, Shanghai 200031, China.
authors.forename: Xue
authors.initials: X
authors.lastname: You
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences , 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031 , China and.
authors.forename: Daqian
authors.initials: D
authors.lastname: Xu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences , 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031 , China and.
authors.forename: Yuxue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences , 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031 , China and.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031, China and.|School of Life Sciences and Technology, Shanghai Tech University, Shanghai 200031, China.
authors.forename: Kaiyang
authors.initials: K
authors.lastname: Man
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences , 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031 , China and.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, New Life Science Building, A2214, Shanghai 200031, China and.|School of Life Sciences and Technology, Shanghai Tech University, Shanghai 200031, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000502:physiology*; D013274:Stomach Neoplasms / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C532354:PAQR3 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1