Yin Bowen, Fan Zhuoyang, Yu Panpan, Li Jin, Wang Yilin, Shu Minfeng
Department of Pharmacology, School of Basic Medical Sciences, Shanghai, Medical College, Fudan University, Shanghai, China.
Key Laboratory of Medical Molecular Virology (Ministry of Education/ National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Front Oncol. 2025 Jun 25;15:1573997. doi: 10.3389/fonc.2025.1573997. eCollection 2025.
Crotonylation, an emerging epigenetic modification, has been implicated in various biological processes, including tumor progression. However, its role in glioma remains poorly understood. This study aims to investigate the prognostic and therapeutic implications of crotonylation-associated genes in glioma.
Crotonylation levels were assessed by IHC in glioma tissues of varying grades. Key crotonylation-associated genes were identified and analyzed across five glioma datasets. A prognostic risk score was developed using machine learning algorithms and validated in multiple cohorts. Genomic alterations, immune landscapes, and therapeutic responses were examined in relation to the risk score. Single-cell dataset GSE131928 was analyzed to explore the relationship between the risk score and immune cell infiltration. After crotonate treatment of T98G cells, ChIP-seq and qPCR were performed to investigate the effect of crotonylation on gene expression. Finally, PD-1 and GZMB expression levels were assessed in glioma tissues with varying crotonylation levels.
Crotonylation levels were negatively correlated with glioma grade. Crotonylation-related genes stratified patients into two subtypes with distinct overall survival outcomes. High-risk patients exhibited increased somatic mutations, specific copy number variations, and an immunosuppressive tumor microenvironment. The risk score correlated positively with TIDE scores, indicating resistance to immune checkpoint blockade therapy. Single-cell analysis revealed a positive association between the risk score and TAM infiltration. Candidate therapeutic agents tailored for high- and low-risk groups were identified. ChIP-seq and qPCR demonstrated that reduced crotonylation suppressed expression and promoted expression in the glioma microenvironment.
Crotonylation-associated genes play a pivotal role in glioma progression and prognosis. The risk score provides a robust tool for patient stratification and treatment guidance, underscoring the importance of crotonylation in glioma biology and its potential as a therapeutic target.
巴豆酰化是一种新兴的表观遗传修饰，已被证明参与包括肿瘤进展在内的各种生物学过程。然而，其在胶质瘤中的作用仍知之甚少。本研究旨在探讨巴豆酰化相关基因在胶质瘤中的预后及治疗意义。
通过免疫组化评估不同级别胶质瘤组织中的巴豆酰化水平。在五个胶质瘤数据集中鉴定并分析关键的巴豆酰化相关基因。使用机器学习算法建立预后风险评分，并在多个队列中进行验证。研究基因组改变、免疫格局和治疗反应与风险评分的关系。分析单细胞数据集GSE131928以探索风险评分与免疫细胞浸润之间的关系。对T98G细胞进行巴豆酸盐处理后，进行染色质免疫沉淀测序（ChIP-seq）和定量聚合酶链反应（qPCR），以研究巴豆酰化对基因表达的影响。最后，评估不同巴豆酰化水平的胶质瘤组织中程序性死亡受体1（PD-1）和颗粒酶B（GZMB）的表达水平。
巴豆酰化水平与胶质瘤级别呈负相关。巴豆酰化相关基因将患者分为两个总生存结果不同的亚型。高危患者表现出体细胞突变增加、特定的拷贝数变异和免疫抑制性肿瘤微环境。风险评分与肿瘤免疫逃逸（TIDE）评分呈正相关，表明对免疫检查点阻断疗法耐药。单细胞分析显示风险评分与肿瘤相关巨噬细胞（TAM）浸润呈正相关。确定了针对高危和低危组的候选治疗药物。ChIP-seq和qPCR表明，巴豆酰化水平降低会抑制胶质瘤微环境中的某些基因表达并促进另一些基因表达。
巴豆酰化相关基因在胶质瘤进展和预后中起关键作用。风险评分为患者分层和治疗指导提供了有力工具，强调了巴豆酰化在胶质瘤生物学中的重要性及其作为治疗靶点的潜力。
