Department of Pediatrics, Qilu Hospital of Shandong University, No.107 West Wenhua Road, Jinan, 250012, Shandong Province, China.
Department of Neurology, Qilu Hospital of Shandong University, No.107 West Wenhua Road, Jinan, 250012, Shandong Province, China.
Sci Rep. 2023 Feb 21;13(1):3023. doi: 10.1038/s41598-023-30248-0.
The repressor element 1 silencing transcription factor (REST) has been proposed to function as a transcription factor to silence gene transcription by binding to repressor element 1 (RE1), a highly conserved DNA motif. The functions of REST in various tumors have been studied, but its role and correlation with immune cell infiltration remains uncertain in gliomas. REST expression was analyzed in datasets of The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) and validated by the Gene Expression Omnibus and Human Protein Atlas databases. The clinical prognosis of REST was evaluated by clinical survival data of TCGA cohort and validated by Chinese Glioma Genome Atlas cohort. MicroRNAs (miRNAs) contributing to REST overexpression in glioma were identified by a combination of a series of in silico analyses, including expression analysis, correlation analysis, and survival analysis. The correlations between immune cell infiltration level and REST expression were analyzed by TIMER2 and GEPIA2 tools. Enrichment analysis of REST was performed using STRING and Metascape tools. The expression and function of predicted upstream miRNAs at REST and their association with glioma malignancy and migration were also confirmed in glioma cell lines. REST was highly expressed and associated with poorer overall survival and disease-specific survival in glioma and some other tumors. MiR-105-5p and miR-9-5p were identified as the most potential upstream miRNAs of REST in glioma patient cohort and experiments in vitro. REST expression was positively correlated with infiltration of immune cells and the expression of immune checkpoints such as PD1/PD-L1 and CTLA-4 in glioma. Furthermore, histone deacetylase 1 (HDAC1) was a potential REST-related gene in glioma. Enrichment analysis of REST found chromatin organization and histone modification were the most significant enriched terms, and Hedgehog-Gli pathway might be involved in the effect of REST on the pathogenesis of glioma. Our study suggests REST to be an oncogenic gene and the biomarker of poor prognosis in glioma. High REST expression might affect the tumor microenvironment of glioma. More basic experiments and large clinical trials aimed at the carcinogenetic study of REST in glioma will be needed in the future.
阻遏元件 1 沉默转录因子（REST）被认为是一种转录因子，通过与高度保守的 DNA 基序 RE1 结合来沉默基因转录。REST 在各种肿瘤中的功能已被研究，但它在神经胶质瘤中的作用及其与免疫细胞浸润的相关性仍不确定。通过分析癌症基因组图谱（TCGA）和基因型-组织表达（GTEx）数据库，对 REST 的表达进行了分析，并通过基因表达综合数据库和人类蛋白质图谱数据库进行了验证。通过 TCGA 队列的临床生存数据评估 REST 的临床预后，并通过中国神经胶质瘤基因组图谱队列进行验证。通过一系列的计算分析，包括表达分析、相关性分析和生存分析，确定了导致神经胶质瘤中 REST 过表达的 microRNAs（miRNAs）。通过 TIMER2 和 GEPIA2 工具分析免疫细胞浸润水平与 REST 表达的相关性。使用 STRING 和 Metascape 工具对 REST 进行富集分析。还在神经胶质瘤细胞系中验证了预测的 REST 上游 miRNAs 的表达和功能及其与神经胶质瘤恶性程度和迁移的关系。在神经胶质瘤和其他一些肿瘤中，REST 表达水平较高，与总生存率和疾病特异性生存率较差相关。在神经胶质瘤患者队列和体外实验中，确定 miR-105-5p 和 miR-9-5p 是 REST 的最具潜力的上游 miRNAs。在神经胶质瘤中，REST 表达与免疫细胞浸润和免疫检查点如 PD1/PD-L1 和 CTLA-4 的表达呈正相关。此外，组蛋白去乙酰化酶 1（HDAC1）是神经胶质瘤中潜在的 REST 相关基因。REST 的富集分析发现染色质组织和组蛋白修饰是最显著的富集项，Hedgehog-Gli 通路可能参与了 REST 对神经胶质瘤发病机制的影响。我们的研究表明 REST 是一种致癌基因，也是神经胶质瘤预后不良的生物标志物。高 REST 表达可能会影响神经胶质瘤的肿瘤微环境。未来需要更多针对 REST 在神经胶质瘤致癌作用的基础实验和大型临床试验。
