PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells
PAQR3 enhances Twist1 degradation to suppress epithelial-mesenchymal transition and metastasis of gastric cancer cells
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PAQR3增强Twist1降解抑制胃癌细胞上皮间质转化和转移
DOI：
10.1093/carcin/bgw013
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发表时间：
2016-04-01
期刊：
影响因子：
4.7
通讯作者：
Chen, Yan
中科院分区：
文献类型：
--
作者：
Guo, Weiwei;You, Xue;Chen, Yan
PAQR 3是一种肿瘤抑制因子，可调节Twist 1的泛素化和降解，Twist 1是肿瘤细胞上皮间质转化的关键因子。Twist 1是PAQR 3抑制小鼠胃癌细胞转移所必需的转录因子，是启动上皮-间质转化（EMT）和促进肿瘤转移所必需的转录因子。PAQR 3是一种新发现的肿瘤抑制因子，在许多类型的人类癌症中经常下调。PAQR 3表达下调与胃癌转移加速和预后不良有关。在这项研究中，我们证明PAQR 3积极参与Twist 1的降解，从而调节胃癌细胞的EMT和转移。PAQR 3过表达降低Twist 1的蛋白水平，但不降低其mRNA水平。Twist 1的蛋白质稳定性和多聚泛素化被PAQR 3改变。PAQR 3与Twist 1和BTRC（一种E3泛素连接酶）形成复合物。PAQR 3增强Twist 1和BTRC之间的相互作用。在PAQR 3和BTRC过表达时，Twist 1从细胞核移动到细胞质中含有蛋白酶体的结构，这是PAQR 3诱导Twist 1降解所必需的。Twist 1蛋白的Twist 1盒结构域是Twist 1与PAQR 3和BTRC相互作用所必需的，是PAQR 3介导的Twist 1降解所必需的。BTRC和Twist 1是PAQR 3抑制胃癌细胞迁移和EMT表型的必要条件。重要的是，Twist 1对于PAQR 3在体内抑制胃癌细胞转移的作用是不可或缺的。总的来说，这些发现不仅指出Twist 1介导PAQR 3对EMT和转移的调节功能，而且还表明靶向Twist 1是通过下调PAQR 3来控制肿瘤转移的有希望的策略。
PAQR3, 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.