PRICKLE3-USP9X interaction-mediated DVL2 deubiquitination promotes the progression of non-small cell lung cancer via canonical WNT pathway.

IF 7.3 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Oncogene Pub Date : 2025-09-19 DOI:10.1038/s41388-025-03580-0

Mengdi Yang, Yudie Lu, Jingrong Zheng, Xinran Zhao, Guangping Wu, Enhua Wang, Huanyu Zhao

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引用次数: 0

Abstract

Prickle planar cell polarity protein 3 (PRICKLE3) is involved in tumor malignant progression. However, little information is available regarding its detailed mechanism in non-small cell lung cancer (NSCLC). The clinicopathological significance of PRICKLE3 in NSCLC specimens was assessed. PRICKLE3-overexpression and PRICKLE3-knockout NSCLC cells were generated in vivo and in vitro. The interaction among PRICKLE3, ubiquitin-specific peptidase 9, X-chromosome (USP9X) and dishevelled2 (DVL2) in NSCLC cells was identified. We found that PRICKLE3 overexpression was correlated with advanced TNM stage, lymphatic metastasis, and poor prognosis in NSCLC patients. PRICKLE3 knockdown inhibited the viability, colony formation, and invasiveness in A549 and H1299 cells, and its overexpression promoted the viability, colony formation, and invasiveness in HBE, H460, and LK2 cells. PRICKLE3 promoted NSCLC growth in vivo. PRICKLE3-DVL2 interaction enhanced the β-catenin phosphorylation at serine 675 for β-catenin nuclear translocation. Furthermore, PRICKLE3 interacted with USP9X to inhibit the DVL2 ubiquitination for the DVL2 stability and the activation of canonical WNT signaling. Overall, we demonstrate a novel signal transduction pathway where PRICKLE3 interacts with USP9X and DVL2 to enhance the DVL2 deubiquitination mediated by USP9X for stabilizing DVL2 expression and activate the canonical WNT signaling for promoting the NSCLC progression.

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针刺3- usp9x相互作用介导的DVL2去泛素化通过典型的WNT途径促进非小细胞肺癌的进展。

刺状平面细胞极性蛋白3 （PRICKLE3）参与肿瘤恶性进展。然而，关于其在非小细胞肺癌（NSCLC）中的详细机制的信息很少。评估了皮刺3在NSCLC标本中的临床病理意义。在体内和体外制备了过表达和敲除的非小细胞肺癌细胞。在非小细胞肺癌细胞中，发现了PRICKLE3、泛素特异性肽酶9、x染色体（USP9X）和dishevelled2 （DVL2）之间的相互作用。我们发现，在NSCLC患者中，PRICKLE3过表达与TNM晚期、淋巴转移和不良预后相关。针刺3敲低抑制A549和H1299细胞的活力、集落形成和侵袭性，过表达促进HBE、H460和LK2细胞的活力、集落形成和侵袭性。在体内，PRICKLE3促进NSCLC生长。PRICKLE3-DVL2相互作用增强了β-catenin 675丝氨酸磷酸化，从而促进了β-catenin核易位。此外，PRICKLE3与USP9X相互作用抑制DVL2泛素化，从而促进DVL2的稳定性和典型WNT信号的激活。总的来说，我们发现了一个新的信号转导途径，其中，PRICKLE3与USP9X和DVL2相互作用，增强USP9X介导的DVL2去泛素化，从而稳定DVL2的表达，并激活典型的WNT信号，促进NSCLC的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oncogene 医学-生化与分子生物学

CiteScore

15.30

自引率

1.20%

发文量

404

审稿时长

1 months

期刊介绍： Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.