USP10通过减弱FOXC1蛋白降解来激活Wnt信号通路，从而促进胰管导管腺癌的进展
USP10 promotes pancreatic ductal adenocarcinoma progression by attenuating FOXC1 protein degradation to activate the WNT signaling pathway
影响因子:10.00000
分区:生物学1区 Top / 生化与分子生物学2区
发表日期:2024
作者:
Jie Wang, Lang Gan, Fenghao Liu, Qin Yang, Qingsong Deng, Di Jiang, Chengcheng Zhang, LeiDa Zhang, XiaoJun Wang
摘要
越来越多的证据表明，泛素特异性蛋白酶10（USP10）是一种去泛素化酶，在靶向蛋白质降解并参与癌症进展中起着至关重要的作用。然而，对USP10和胰管导管腺癌（PDAC）之间的关系知之甚少。在这里，我们开发了一个靶向USP的siRNA库，结合了患者来源的PDAC细胞中功能丧失的实验屏幕。这种方法将USP10确定为PDAC细胞迁移的主要调节剂。在PDAC患者组织中观察到了高USP10表达水平，这与预后不良有关。此外，USP10表达的敲低抑制了PDAC细胞的增殖和体内和体外迁移。从机械上讲，USP10通过去泛素化提高了FOXC1蛋白质的稳定性。 S272a上FOXC1的磷酸化取决于USP10介导的FOXC1去泛素化。另外，USP10促进了核中FOXC1蛋白的定位。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之间存在正反馈循环，可以激活Wnt信号传导，从而促进PDAC恶性肿瘤的进展。因此，USP10代表了一个令人兴奋的治疗靶标，可以支持治疗PDAC的新策略。
Abstract
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.