Zhou Zheng, Wang Bing-Zhi, Zhang Chaoqi, Zhang Guochao, Wu Peng, Dong Xin, Sun Nan, He Jie
Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, China.
Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Immunother Cancer. 2025 Aug 25;13(8):e012539. doi: 10.1136/jitc-2025-012539.
Ubiquitination-a pivotal post-translational modification that orchestrates cellular homeostasis and oncogenic pathways-remains underexplored as a pancancer regulatory hub. Although ubiquitination dysregulation is linked to tumor progression, a comprehensive, multicancer framework integrating prognostic, molecular, and microenvironmental landscapes is lacking.
This study integrated data of 4,709 patients from 26 cohorts across five solid tumor types (lung cancer, esophageal cancer, cervical cancer, urothelial cancer, and melanoma) and mapped the molecular profiles to the interaction network. Cox regression and the Kaplan-Meier survival method were employed for prognostic analysis. Functional enrichment and protein-protein interaction analyses were performed to identify the key downstream pathways and genes. Findings were validated using independent patient cohorts, cell line models, and in vivo experiments.
Key nodes and prognostic pathways within the ubiquitination-modification network were identified. A conserved ubiquitination-related prognostic signature (URPS) effectively stratified patients into high-risk and low-risk groups with distinct survival outcomes across all analyzed cancers. URPS may serve as a novel biomarker for predicting immunotherapy response, with the potential to identify patients who are more likely to benefit from immunotherapy in clinical settings. A comprehensive analysis of URPS-associated proteins revealed novel cancer-related interaction partners as potential drug targets. At the single-cell resolution, URPS enabled more precise classification of distinct cell types and was associated with macrophage infiltration within the tumor microenvironment. In vivo, in vitro, and patient cohort analyses, demonstrated that OTUB1-TRIM28 ubiquitination plays a crucial role in modulating MYC pathway and influencing patient prognosis.
We constructed a pancancer ubiquitination regulatory network and prognostic model, revealing important pathways, and offering insights into predicting patient prognosis and understanding biological mechanisms.
泛素化——一种协调细胞内稳态和致癌途径的关键翻译后修饰——作为一种泛癌调节枢纽仍未得到充分研究。尽管泛素化失调与肿瘤进展有关，但缺乏一个整合预后、分子和微环境格局的全面多癌框架。
本研究整合了来自五种实体瘤类型（肺癌、食管癌、宫颈癌、尿路上皮癌和黑色素瘤）的26个队列的4709名患者的数据，并将分子谱映射到相互作用网络。采用Cox回归和Kaplan-Meier生存方法进行预后分析。进行功能富集和蛋白质-蛋白质相互作用分析以确定关键的下游途径和基因。使用独立的患者队列、细胞系模型和体内实验对结果进行验证。
确定了泛素化修饰网络内的关键节点和预后途径。一个保守的泛素化相关预后特征（URPS）有效地将患者分为高风险和低风险组，在所有分析的癌症中具有不同的生存结果。URPS可能作为预测免疫治疗反应的新型生物标志物，有可能在临床环境中识别更可能从免疫治疗中受益的患者。对URPS相关蛋白的综合分析揭示了新的癌症相关相互作用伙伴作为潜在的药物靶点。在单细胞分辨率下，URPS能够更精确地分类不同的细胞类型，并与肿瘤微环境中的巨噬细胞浸润相关。体内、体外和患者队列分析表明，OTUB1-TRIM28泛素化在调节MYC途径和影响患者预后中起关键作用。
我们构建了一个泛癌泛素化调控网络和预后模型，揭示了重要途径，并为预测患者预后和理解生物学机制提供了见解。
