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

USP10 promotes pancreatic ductal adenocarcinoma progression by attenuating FOXC1 protein degradation to activate the WNT signaling pathway

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International Journal of Biological Sciences

影响因子:10

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

DOI: 10.7150/ijbs.92278

摘要

越来越多的证据表明，去泛素酶USP10在靶向蛋白降解中发挥关键作用，并参与癌症进展。然而，USP10与胰腺导管腺癌（PDAC）之间的关系尚不明确。本研究建立了针对USP的siRNA文库，并结合来自患者来源的PDAC细胞的功能筛选，鉴定出USP10作为PDAC细胞迁移的主调控因子。在PDAC患者组织中观察到高水平的USP10表达，且与预后不良相关。此外，USP10的敲低在体内外均抑制了PDAC细胞的增殖和迁移。机制上，USP10通过去泛素化增加FOXC1蛋白的稳定性。FOXC1在S272A位点的磷酸化依赖于USP10介导的去泛素化。此外，USP10促进FOXC1蛋白在细胞核中的定位。值得注意的是，FOXC1还能通过转录激活增加USP10的mRNA表达水平。研究数据显示，USP10与FOXC1之间存在正反馈环路，能激活WNT信号通路，从而促进PDAC的恶性进展。因此，USP10作为一个具有潜力的治疗靶点，有望为PDAC的治疗策略提供新的思路。

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.