Long Deyu, Xue Yajing, Yu Xiushi, Qin Xue, Chen Jiaxin, Luo Jia, Ma Ketao, Wei Lili, Li Xinzhi
The Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University Medical College, Shihezi 832000, China.
Department of Physiology, Shihezi University School of Medicine, Shihezi 832003, China.
Int J Mol Sci. 2025 Jul 6;26(13):6501. doi: 10.3390/ijms26136501.
Ubiquitination is a dynamic and reversible post-translational modification mediated by ubiquitination regulators (UBRs), which plays an essential role in protein stability, cell differentiation and immunity. Dysregulation of UBRs can lead to destabilization of biological processes and may induce serious human diseases, including cancer. Many UBRs, such as E3 ubiquitin ligases and deubiquitinases (DUBs), have been identified as potential drug targets for cancer therapy. However, the potential clinical value of UBRs in lung adenocarcinoma (LUAD) remains to be elucidated. Here, we identified 17 hub UBRs from high-confidence protein-protein interaction networks of UBRs correlated with cancer hallmark-related pathways using four topological algorithms. The expression of hub UBRs is affected by copy number variation and post-transcriptional regulation, and their high expression is often detrimental to patient survival. Based on the expression profiles of hub UBRs, patients can be classified into two ubiquitination subtypes with different characteristics. These subtypes exhibit significant differences across multiple dimensions, including survival, expression level, mutation burden, female predominance, infiltration level, immune profile, and drug response. In addition, we established a scoring system for evaluating the ubiquitination status of individual LUAD patients, called the ubiquitination-related risk (UB_risk) score, and found that patients with low scores are more likely to gain advantages from immunotherapy. The results of this study emphasize the critical role of ubiquitination in the classification, tumor microenvironment and immunotherapy of LUAD. The construction of the UB_risk scoring system lays a research foundation for evaluating the ubiquitination status of individual LUAD patients and formulating precise treatment strategies from the ubiquitination level.
泛素化是一种由泛素化调节因子（UBR）介导的动态且可逆的翻译后修饰，它在蛋白质稳定性、细胞分化和免疫中起着至关重要的作用。UBR的失调会导致生物过程的不稳定，并可能引发包括癌症在内的严重人类疾病。许多UBR，如E3泛素连接酶和去泛素化酶（DUB），已被确定为癌症治疗的潜在药物靶点。然而，UBR在肺腺癌（LUAD）中的潜在临床价值仍有待阐明。在此，我们使用四种拓扑算法，从与癌症特征相关通路相关的UBR的高置信度蛋白质-蛋白质相互作用网络中鉴定出17个核心UBR。核心UBR的表达受拷贝数变异和转录后调控的影响，其高表达通常对患者生存不利。基于核心UBR的表达谱，患者可被分为具有不同特征的两种泛素化亚型。这些亚型在多个维度上表现出显著差异，包括生存、表达水平、突变负担、女性优势、浸润水平、免疫特征和药物反应。此外，我们建立了一个用于评估个体LUAD患者泛素化状态的评分系统，称为泛素化相关风险（UB_risk）评分，并发现得分低的患者更有可能从免疫治疗中获益。本研究结果强调了泛素化在LUAD的分类、肿瘤微环境和免疫治疗中的关键作用。UB_risk评分系统的构建为评估个体LUAD患者的泛素化状态以及从泛素化水平制定精准治疗策略奠定了研究基础。
