Accumulating evidence suggests that p53 plays a suppressive role in cancer metastasis, yet the underlying mechanism remains largely unclear. Regulation of actin dynamics is essential for the control of cell migration, which is an important step in metastasis. The Arp2/3 complex is a major nucleation factor to initiate branched actin polymerization that drives cell migration. However, it is unknown whether p53 could suppress metastasis through modulating Arp2/3 function. Here, we report that WDR63 is transcriptionally upregulated by p53. We show with migration assays and mouse xenograft models that WDR63 negatively regulates cell migration, invasion, and metastasis downstream of p53. Mechanistically, WDR63 interacts with the Arp2/3 complex and inhibits Arp2/3-mediated actin polymerization. Furthermore, WDR63 overexpression is sufficient to dampen the increase in cell migration, invasion, and metastasis induced by p53 depletion. Together, these findings suggest that WDR63 is an important player in the regulation of Arp2/3 function and also implicate WDR63 as a critical mediator of p53 in suppressing metastasis.

中文翻译：

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WDR63 抑制 Arp2/3 依赖性肌动蛋白聚合并介导 p53 在抑制转移中的功能。

越来越多的证据表明 p53 在癌症转移中起抑制作用，但其潜在机制仍不清楚。肌动蛋白动力学的调节对于控制细胞迁移至关重要，这是转移的重要步骤。Arp2/3 复合物是启动驱动细胞迁移的支链肌动蛋白聚合的主要成核因子。然而，尚不清楚p53是否可以通过调节Arp2/3功能来抑制转移。在这里，我们报告 WDR63 被 p53 转录上调。我们通过迁移测定和小鼠异种移植模型显示 WDR63 负调控 p53 下游的细胞迁移、侵袭和转移。从机制上讲，WDR63 与 Arp2/3 复合物相互作用并抑制 Arp2/3 介导的肌动蛋白聚合。此外，WDR63 过表达足以抑制 p53 耗竭诱导的细胞迁移、侵袭和转移的增加。总之，这些发现表明 WDR63 是调节 Arp2/3 功能的重要参与者，并且还暗示 WDR63 作为 p53 在抑制转移中的关键介质。