RND3 promotes Snail 1 protein degradation and inhibits glioblastoma cell migration and invasion.
RND3 promotes Snail 1 protein degradation and inhibits glioblastoma cell migration and invasion.
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RND3促进Snail 1蛋白降解并抑制胶质母细胞瘤细胞迁移和侵袭
DOI：
10.18632/oncotarget.12396
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发表时间：
2016-12-13
期刊：
影响因子：
--
通讯作者：
Chang J
中科院分区：
文献类型：
--
作者：
Liu B;Dong H;Lin X;Yang X;Yue X;Yang J;Li Y;Wu L;Zhu X;Zhang S;Tian D;Wang J;Cai Q;Mao S;Chen Q;Chang J
Snail 1信号的激活促进多种肿瘤的迁移和侵袭，包括多形性胶质母细胞瘤（GBM）。然而，在GBM细胞迁移和侵袭过程中增强Snail 1信号传导的分子机制在很大程度上仍然未知。确定调节Snail 1信号传导的因子对于阻断肿瘤细胞迁移和侵袭至关重要。通过筛选人GBM标本，我们发现小GTCRND 3的表达水平与E-cadherin和claudin的表达水平呈正相关，这两种胶质母细胞瘤迁移生物标志物受Snail 1负调控。E-钙粘蛋白和密蛋白的下调与GBM细胞的迁移和侵袭有关。我们证明了RND 3作为Snail指导的转录调控的内源性抑制剂发挥作用。RND 3与Snail 1蛋白发生物理相互作用，增强Snail 1的泛素化，促进蛋白降解。RND 3的强制表达抑制了Snail 1的活性，进而在体外细胞培养和体内GBM异种移植小鼠中阻断了胶质母细胞瘤细胞的迁移和侵袭。相反，下调RND 3增强Snail 1活性，随后降低E-cadherin表达，最终促进胶质母细胞瘤细胞的迁移和侵袭。Snail 1敲低可减弱RND 3下调诱导的促迁移作用。这些发现部分解释了为什么Snail 1活性在GBM中增强，并定义了RND 3在GBM细胞迁移和侵袭中的新功能。
Activation of Snail1 signaling promotes the migration and invasion of multiple tumors, including glioblastoma multiforme (GBM). However, the molecular mechanism that augments Snail1 signaling during GBM cell migration and invasion remains largely unknown. Identification of the factors that regulate Snail1 signaling is critical to block tumor cell migration and invasion. By screening human GBM specimens, we found that the expression levels of small GTPase RND3 positively correlated with the expression levels of E-cadherin and claudin, the glioblastoma migration biomarkers negatively regulated by Snail1. Downregulation of E-cadherin and claudin has been associated with the migration and invasion of GBM cells. We demonstrated that RND3 functioned as an endogenous inhibitor of the Snail-directed transcriptional regulation. RND3 physically interacted with Snail1 protein, enhanced Snail1 ubiquitination, and facilitated the protein degradation. Forced expression of RND3 inhibited Snail1 activity, which in turn blocked glioblastoma cell migration and invasion in vitro in cell culture and in vivo in GBM xenograft mice. In contrast, downregulation of RND3 augmented Snail1 activity, and subsequently decreased E-cadherin expression, eventually promoted glioblastoma cell migration and invasion. The pro-migration induced by RND3 downregulation was attenuated by Snail1 knockdown. The findings partially explain why Snail1 activity is augmented in GBM, and defines a new function of RND3 in GBM cell migration and invasion.