越来越多的证据表明，泛素特异性蛋白酶 10 (USP10)（一种去泛素化酶）在靶向蛋白质降解中发挥重要作用，并参与癌症进展。然而，USP10 与胰腺导管腺癌 (PDAC) 之间的关系尚不清楚。在这里，我们开发了一个 USP 靶向 siRNA 文库，结合了患者来源的 PDAC 细胞的功能丧失实验筛选。该方法将 USP10 确定为 PDAC 细胞迁移的主要调节因子。在 PDAC 患者组织中观察到 USP10 高表达水平，这与不良预后相关。此外，USP10表达的敲低抑制了PDAC细胞在体内和体外的增殖和迁移。从机制上讲，USP10 通过去泛素化增加了 FOXC1 蛋白的稳定性。 FOXC1 在 S272A 处的磷酸化依赖于 USP10 介导的 FOXC1 去泛素化。此外，USP10 促进 FOXC1 蛋白在细胞核中的定位。有趣的是，FOXC1 可以通过转录激活增加 USP10 mRNA 表达水平。我们的数据表明，USP10 和 FOXC1 之间存在正反馈环，可以激活 WNT 信号传导，从而促进 PDAC 恶性进展。因此，USP10 代表了一个令人兴奋的治疗靶点，可以支持治疗 PDAC 的新策略。© 作者。

Increasing evidence has suggested that ubiquitin-specific protease 10 (USP10), a deubiquitinating enzyme, plays an essential role in targeted protein degradation and participates in cancer progression. However, the relationship between USP10 and pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we developed a USP-targeting siRNA library, combining a loss-of-function experimental screen in patient-derived PDAC cells. This approach identified USP10 as a master regulator of PDAC cell migration. High USP10 expression levels were observed in PDAC patient tissues, which were associated with poor prognosis. Furthermore, knockdown of USP10 expression inhibited PDAC cell proliferation and migration in vivo and in vitro. Mechanistically, USP10 increased FOXC1 protein stability via deubiquitination. The phosphorylation of FOXC1 at S272A was dependent on USP10-mediated deubiquitination of FOXC1. Additionally, USP10 promoted FOXC1 protein localization in the nucleus. Interestingly, FOXC1 could increase USP10 mRNA expression levels by transcriptional activation. Our data suggest that a positive feedback loop exists between USP10 and FOXC1 that can activate WNT signaling, thus facilitating PDAC malignant progression. Therefore, USP10 represents an exciting therapeutic target that could support new strategies for treating PDAC.© The author(s).