USP14 promotes the cancer stem-like cell properties of OSCC via promoting SOX2 deubiquitination.

IF 2.9 3区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Oral diseases Pub Date : 2024-10-01 Epub Date: 2024-02-20 DOI:10.1111/odi.14896

Chang Liu, Shijie Zhou, Wei Tang

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引用次数: 0

Abstract

Objective: USP14 (Ubiquitin-specific-processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem-like cells (CSCs) in OSCC.

Materials and methods: Bioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient-derived cells were used for experimental validation, employing co-immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes.

Results: USP14 upregulation was associated with worse overall survival and progression-free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl-terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild-type USP14, but not the hydrolase-deficient-mutant USP14^C114A, enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation in vitro and tumor growth in vivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2. These findings were verified in OSCC patient-derived CSC cells.

Conclusion: This study revealed a USP14-SOX2 axis regulating the CSC properties of OSCC.

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USP14 通过促进 SOX2 的去泛素化促进 OSCC 的癌干样细胞特性。

目的：USP14（泛素特异性加工蛋白酶14）是一种在口腔鳞状细胞癌（OSCC）中具有致癌作用的去泛素化酶。本研究旨在鉴定 USP14 的新底物，并阐明它们在调节 OSCC 中癌症干样细胞（CSCs）中的作用：分别使用 UbiBrowser 2.0 和 HDOCK 进行生物信息学预测和对接。采用共免疫沉淀、环己亚胺追逐试验和肿瘤球形成等方法对 OSCC 细胞系和患者衍生细胞进行实验验证，以评估 USP14 对 SOX2 稳定性、泛素化和 CSC 表型的影响：结果：USP14的上调与OSCC总生存期和无进展间隔期的恶化有关。USP14通过其泛素羧基末端水解酶结构域与SOX2相互作用。USP14 基因敲除会增加 SOX2 的多泛素化，从而影响其稳定性。异位过表达野生型 USP14（而非水解酶缺陷突变体 USP14C114A）可通过减少多泛素化来增强 SOX2 的稳定性。USP14 基因敲除抑制了体外 OSCC 细胞增殖、集落形成和肿瘤球形成以及体内肿瘤生长。然而，过表达 SOX2 可减轻 USP14 敲除后 CSC 标记的减少。这些发现在源自 OSCC 患者的 CSC 细胞中得到了验证：本研究揭示了调控 OSCC CSC 特性的 USP14-SOX2 轴。

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

Oral diseases 医学-牙科与口腔外科

CiteScore

7.60

自引率

5.30%

发文量

325

审稿时长

4-8 weeks

期刊介绍： Oral Diseases is a multidisciplinary and international journal with a focus on head and neck disorders, edited by leaders in the field, Professor Giovanni Lodi (Editor-in-Chief, Milan, Italy), Professor Stefano Petti (Deputy Editor, Rome, Italy) and Associate Professor Gulshan Sunavala-Dossabhoy (Deputy Editor, Shreveport, LA, USA). The journal is pre-eminent in oral medicine. Oral Diseases specifically strives to link often-isolated areas of dentistry and medicine through broad-based scholarship that includes well-designed and controlled clinical research, analytical epidemiology, and the translation of basic science in pre-clinical studies. The journal typically publishes articles relevant to many related medical specialties including especially dermatology, gastroenterology, hematology, immunology, infectious diseases, neuropsychiatry, oncology and otolaryngology. The essential requirement is that all submitted research is hypothesis-driven, with significant positive and negative results both welcomed. Equal publication emphasis is placed on etiology, pathogenesis, diagnosis, prevention and treatment.