Deubiquitinase PSMD14 promotes tumorigenicity of glioblastoma by deubiquitinating and stabilizing β‐catenin

IF 5 3区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

BioFactors Pub Date : 2024-05-02 DOI:10.1002/biof.2061

Yang Wang, Yu Liu, Chongchen Ma, Cen Liu, Qikai Tang, Zhangjie Wang, Jiacheng Lu, Zhengxin Chen, Huibo Wang

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引用次数: 0

Abstract

The deubiquitinating enzyme 26S proteasome non‐ATPase regulatory subunit 14 (PSMD14), a member of the JAB1/MPN/Mov34 metalloenzyme (JAMM) family, has been shown to function as an oncogene in various human cancers. However, the function of PSMD14 in glioma and the underlying mechanism remain unclear. In this study, our findings reveal a dramatic upregulation of PSMD14 in GBMs, which is associated with poor survival outcomes. Knocking down PSMD14 is associated with decreased proliferation and invasion of GBM cells in vitro and inhibited tumor growth in a xenograft mouse model. Mechanistically, PSMD14 directly interacts with β‐catenin, leading to a decrease in the K48‐linked ubiquitination of β‐catenin and subsequent β‐catenin stabilization. Increased β‐catenin expression significantly reverses the inhibitory effects of PSMD14 knockdown on the migration, invasion, and tumor growth of GBM cells. Moreover, we observed a significant correlation between PSMD14 and β‐catenin expression in human GBM samples. In summary, our results reveal that PSMD14 is a crucial deubiquitinase that is responsible for stabilizing the β‐catenin protein, highlighting its potential for use as a therapeutic target for GBM.

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去泛素化酶PSMD14通过去泛素化和稳定β-catenin促进胶质母细胞瘤的致瘤性

去泛素化酶26S蛋白酶体非ATP酶调节亚基14（PSMD14）是JAB1/MPN/Mov34金属酶（JAMM）家族的成员之一，已被证明在多种人类癌症中起着癌基因的作用。然而，PSMD14 在胶质瘤中的功能及其内在机制仍不清楚。在这项研究中，我们的发现揭示了 PSMD14 在胶质瘤中的显著上调，这与不良的生存结果有关。敲除 PSMD14 可减少 GBM 细胞在体外的增殖和侵袭，并抑制异种移植小鼠模型中的肿瘤生长。从机理上讲，PSMD14直接与β-catenin相互作用，导致与K48连接的β-catenin泛素化减少，β-catenin随之稳定。β-catenin表达的增加能显著逆转PSMD14敲除对GBM细胞迁移、侵袭和肿瘤生长的抑制作用。此外，我们还观察到 PSMD14 与人类 GBM 样本中的β-catenin 表达之间存在明显的相关性。总之，我们的研究结果表明，PSMD14 是一种重要的去泛素化酶，负责稳定 β-catenin 蛋白，这突显了它作为 GBM 治疗靶点的潜力。

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

BioFactors 生物-内分泌学与代谢

CiteScore

11.50

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： BioFactors, a journal of the International Union of Biochemistry and Molecular Biology, is devoted to the rapid publication of highly significant original research articles and reviews in experimental biology in health and disease. The word “biofactors” refers to the many compounds that regulate biological functions. Biological factors comprise many molecules produced or modified by living organisms, and present in many essential systems like the blood, the nervous or immunological systems. A non-exhaustive list of biological factors includes neurotransmitters, cytokines, chemokines, hormones, coagulation factors, transcription factors, signaling molecules, receptor ligands and many more. In the group of biofactors we can accommodate several classical molecules not synthetized in the body such as vitamins, micronutrients or essential trace elements. In keeping with this unified view of biochemistry, BioFactors publishes research dealing with the identification of new substances and the elucidation of their functions at the biophysical, biochemical, cellular and human level as well as studies revealing novel functions of already known biofactors. The journal encourages the submission of studies that use biochemistry, biophysics, cell and molecular biology and/or cell signaling approaches.