UBE2S promotes gastric cancer progression through RACGAP1 stabilization associated with K292-dependent K63-linked ubiquitination.

IF 5.7 4区医学 Q2 ONCOLOGY

Cancer Biology & Therapy Pub Date : 2026-12-31 Epub Date: 2026-10-08 DOI:10.1080/15384047.2026.2737476

HeFei Cheng, Ziqing Zhou, Qirun Cheng, Ziqi Sui

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引用次数: 0

Abstract

Objective: Gastric cancer (GC) remains highly lethal, and effective molecular targets are limited. This study investigated the expression, exploratory survival associations, and mechanistic role of UBE2S in GC.

Methods: UBE2S expression and survival associations were analyzed using public datasets, whereas UBE2S protein expression was assessed in seven paired GC tissues and GC cell lines. Loss- and gain-of-function assays, xenograft models, quantitative proteomics, genetic rescue, JNK inhibition, co-immunoprecipitation, cycloheximide chase, proteasome inhibition, and linkage-specific ubiquitination assays were performed.

Results: UBE2S was upregulated in GC and showed apparent within-dataset discriminatory ability at the tissue-transcript level (AUC = 0.909); higher expression showed an exploratory association with unfavorable survival in public datasets. Protein assessment in seven paired tissues was consistent with this expression pattern. UBE2S depletion suppressed GC cell viability, clonogenicity, migration, and xenograft growth. Proteomics prioritized RACGAP1 as a candidate downstream effector, and subsequent rescue experiments supported its functional relevance. UBE2S associated with RACGAP1 and increased RACGAP1 protein stability without altering its mRNA expression. UBE2S depletion decreased K63-linked and increased K48-linked ubiquitination of RACGAP1, whereas MG132 partially restored RACGAP1 abundance. K292 mutation impaired UBE2S-dependent K63-linked ubiquitination, RACGAP1 accumulation, JNK/c-Jun activation, and malignant phenotypes, although RACGAP1-K292R retained partial activity. Pharmacological JNK inhibition with SP600125 suppressed RACGAP1-mediated JNK/c-Jun reactivation and clonogenic rescue.

Conclusion: Our findings support a model in which UBE2S promotes GC progression by stabilizing RACGAP1 in association with K292-dependent K63-linked ubiquitination, providing a mechanistic basis for further preclinical investigation of the UBE2S/RACGAP1/JNK/c-Jun axis.

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UBE2S通过与k292依赖性k63连接泛素化相关的RACGAP1稳定促进胃癌进展。

目的：胃癌（GC）仍然具有高致死率，有效的分子靶点有限。本研究探讨了UBE2S在胃癌中的表达、探索性生存关联及其机制作用。方法：使用公共数据集分析UBE2S的表达和生存相关性，同时评估7对GC组织和GC细胞系中UBE2S蛋白的表达。进行了功能丧失和功能获得分析、异种移植模型、定量蛋白质组学、遗传拯救、JNK抑制、共免疫沉淀、环己亚胺追踪、蛋白酶体抑制和连锁特异性泛素化分析。结果：UBE2S在GC中表达上调，在组织转录水平上表现出明显的数据集内区分能力（AUC = 0.909）；在公共数据集中，高表达与不利的生存存在探索性关联。7个配对组织的蛋白评估与这种表达模式一致。UBE2S耗竭抑制GC细胞活力、克隆原性、迁移和异种移植物生长。蛋白质组学将RACGAP1优先作为候选下游效应物，随后的拯救实验支持其功能相关性。UBE2S与RACGAP1相关，在不改变其mRNA表达的情况下增加了RACGAP1蛋白的稳定性。UBE2S缺失降低了k63连接的RACGAP1泛素化，增加了k48连接的RACGAP1泛素化，而MG132部分恢复了RACGAP1的丰度。尽管RACGAP1- k292r保留了部分活性，但K292突变破坏了ube2s依赖性k63连锁泛素化、RACGAP1积累、JNK/c-Jun激活和恶性表型。SP600125抑制JNK抑制了racgap1介导的JNK/c-Jun再激活和克隆拯救。结论：我们的研究结果支持了UBE2S通过稳定RACGAP1与k292依赖性k63连锁泛素化相关而促进GC进展的模型，为进一步研究UBE2S/RACGAP1/JNK/c-Jun轴提供了机制基础。

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

Cancer Biology & Therapy 医学-肿瘤学

CiteScore

7.00

自引率

0.00%

发文量

审稿时长

2.3 months

期刊介绍： Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.