Systematic analysis identifies REST as an oncogenic and immunological biomarker in glioma

Abstract

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.