USP10 通过抑制 FOXC1 蛋白降解来激活 WNT 信号通路,从而促进胰腺导管腺癌的进展。

IF 8.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
International Journal of Biological Sciences Pub Date : 2024-09-30 eCollection Date: 2024-01-01 DOI:10.7150/ijbs.92278
Jie Wang, Lang Gan, Fenghao Liu, Qin Yang, Qingsong Deng, Di Jiang, Chengcheng Zhang, LeiDa Zhang, XiaoJun Wang
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引用次数: 0

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,在有针对性的蛋白质降解过程中发挥着重要作用,并参与癌症进展。然而,人们对 USP10 与胰腺导管腺癌(PDAC)之间的关系知之甚少。在这里,我们开发了一个 USP 靶向 siRNA 文库,并结合了在源自患者的 PDAC 细胞中进行的功能缺失实验筛选。这种方法确定了 USP10 是 PDAC 细胞迁移的主调控因子。在 PDAC 患者组织中观察到 USP10 的高表达水平,这与预后不良有关。此外,敲除 USP10 的表达抑制了 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 还促进了 FOXC1 蛋白在细胞核中的定位。有趣的是,FOXC1 可以通过转录激活提高 USP10 mRNA 的表达水平。我们的数据表明,USP10 和 FOXC1 之间存在正反馈回路,可以激活 WNT 信号,从而促进 PDAC 的恶性进展。因此,USP10 是一个令人兴奋的治疗靶点,可支持治疗 PDAC 的新策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
USP10 promotes pancreatic ductal adenocarcinoma progression by attenuating FOXC1 protein degradation to activate the WNT signaling pathway.

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.

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来源期刊
International Journal of Biological Sciences
International Journal of Biological Sciences 生物-生化与分子生物学
CiteScore
16.90
自引率
1.10%
发文量
413
审稿时长
1 months
期刊介绍: The International Journal of Biological Sciences is a peer-reviewed, open-access scientific journal published by Ivyspring International Publisher. It dedicates itself to publishing original articles, reviews, and short research communications across all domains of biological sciences.
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