FBXO31 Suppresses Gastric Cancer EMT by Targeting Snail1 for Proteasomal Degradation
FBXO31 Suppresses Gastric Cancer EMT by Targeting Snail1 for Proteasomal Degradation
复制标题
FBXO31 通过靶向 Snail1 进行蛋白酶体降解来抑制胃癌 EMT
DOI：
10.1158/1541-7786.mcr-17-0432
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发表时间：
2018-02-01
影响因子：
5.2
通讯作者：
Liu, Zhifang
中科院分区：
文献类型：
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作者：
Zou, Shuiyan;Ma, Cunying;Liu, Zhifang
F-box蛋白FBXO 31是Skp 1/Cul 1/F-box（SCF）E3泛素连接酶复合物的一个组成部分，在神经元发育、应激反应和肿瘤发生中起着重要的调节作用。我们最近的研究表明，FBXO 31在胃癌中具有抑癌作用，FBXO 31蛋白的缺失与较高的恶性表型和较差的预后相关。然而，人们对潜在的机制知之甚少。在这项研究中，FBXO 31通过抑制上皮-间质转化（EMT）来抑制胃癌进展。FBXO 31过表达分别降低EMT转录因子Snail 1（SNAI 1）的蛋白水平，而其抑制则增加EMT转录因子Snail 1（SNAI 1）的蛋白水平。进一步的证据表明，FBXO 31与Snail 1相互作用，并介导胃癌中Snail 1的泛素和蛋白酶体依赖性降解。FBXO 31的F-box结构域和Snail 1的磷酸化是FBXO 31与Snail 1相互作用所必需的。小鼠模型实验表明，FBXO 31过表达抑制胃癌细胞的体内定植。此外，FBXO 31和蜗牛1之间的高度显着的负相关性在人胃癌临床标本中得到验证。综上所述，这些发现确定Snail 1为FBXO 31在胃癌中的新靶蛋白，并证实FBXO 31在胃癌进展和转移中的新调节作用。含义：这些发现表明FBXO 31通过泛素介导的Snail 1降解在胃癌中发挥肿瘤抑制作用，这代表了FBXO 31激活剂在胃癌预防和治疗中的可行策略。Mol Cancer Res; 16（2）; 286-95.©2017 AACR.
The F-box protein FBXO31, a component of the Skp1/Cul1/F-box (SCF) E3 ubiquitin ligase complex, plays an important regulatory role in neuronal development, stress response, and tumorigenesis. Our recent report indicates that FBXO31 functions as a tumor suppressor in gastric cancer, and the loss of FBXO31 protein is associated with a higher malignant phenotype and poorer prognosis. However, little is known about the underlying mechanism. In this study, FBXO31 inhibits gastric cancer progression by suppressing the epithelial–mesenchymal transition (EMT). FBXO31 overexpression decreases, whereas its inhibition increases, the protein level of the EMT transcription factor Snail1 (SNAI1), respectively. Further evidence demonstrates that FBXO31 interacts with Snail1 and mediates the ubiquitin- and proteasome-dependent degradation of Snail1 in gastric cancer. The F-box domain of FBXO31 and the phosphorylation of Snail1 are necessary for the molecular interaction between FBXO31 and Snail1. Mouse modeling experiments reveal that FBXO31 overexpression inhibits in vivo colonization of gastric cancer cells. Furthermore, a highly significant negative correlation between FBXO31 and Snail1 is validated in human gastric cancer clinical specimens. Taken together, these findings identify Snail1 as a new target protein of FBXO31 in gastric cancer and substantiate a novel regulatory role of FBXO31 on gastric cancer progression and metastasis. Implication: These findings demonstrate that FBXO31 exerts the tumor-inhibitory role in gastric cancer by ubiquitin-mediated degradation of Snail1, which represents a viable strategy of FBXO31 activators in the prevention and therapy of gastric cancer. Mol Cancer Res; 16(2); 286–95. ©2017 AACR.