Exploring the role of m6A methylation regulators in glioblastoma multiforme and their impact on the tumor immune microenvironment

Abstract

Although the role of N6‐Methyladenosine (m6A) methylation factors has been established in multiple cancer types, its involvement in glioblastoma multiforme (GBM) remains limited. This study aims to explore the involvement of m6A regulators in GBM and examine their association with the tumor immune microenvironment (TIME). A comprehensive set of 24 candidate m6A RNA regulators was procured. Consensus clustering was performed based on these regulators to identify distinct GBM clusters. PD‐L1 and PD‐1 levels, immune cell infiltration, and immune scores were evaluated between two clusters. Prognostic signatures and correlation analysis with TIME were analyzed using Lasso and Spearman's analysis. GBM tissue was collected to verify the correlations. Eighteen m6A regulators (WTAP, YTHDF2, HNRNPC, CAPRIN1, YTHDF3, METTL14, GNL3, ZCCHC4, HNRNPD, YTHDF1, RBM15, PCIF1, RBM27, KIAA1429, MSI2, FTO, ALKBH5, and METTL3), PD‐L1, and PD‐1 were significantly upregulated in GBM tissue. These regulators were divided into two distinct molecular subtypes (clusters 1 and 2). Cluster 2 exhibited a significant increase in immune score, monocytes, M1 macrophages, activated mast cells, and eosinophils. HNRNPC, YWHAG, and ALKBH5 were significantly associated with TIME and positively correlated with PD‐L1. Immune cell invasiveness profiles dynamically changed with copy number changes of these three m6A regulators. Finally, YWHAG and ALKBH5 were found to be independent prognostic indicators of GBM through risk analysis and were experimentally verified with clinical samples. YWHAG and ALKBH5 may be used as prognostic markers for patients with GBM. m6A methylation regulators may play an important role in regulating PD‐L1/PD‐1 expression and immune infiltration, thus having a significant impact on GBM TIME.

Exploring the prognostic potential of m6A methylation regulators in low-grade glioma: implications for tumor microenvironment modulation

“…m6A methylation has been shown to regulate mRNA degradation and translation, thereby affecting gene expression [ 40 ]. In immune cells, the expression levels of some genes may be regulated by m6A methylation, thereby affecting the function and infiltration of immune cells [ 41 ]. According to our findings, m6A methylation may regulate factors related to immune suppression, such as PD-L1 and PD-1.…”

Emerging Roles and Mechanisms of RNA Modifications in Neurodegenerative Diseases and Glioma

“…Furthermore, YTHDF2’s role extends to immune regulation, where its deficiency impairs the stability of ZDHHC3 mRNA, affecting PD-L1 expression and degradation in glioma [ 148 ]. YTHDF2 is also involved in key signaling pathways, including the receptor tyrosine kinase MET pathway, which is essential for glioblastoma stem cell renewal and tumorigenicity [ 166 ]. Its expression correlates with various immune cells in low-grade gliomas, and it has been shown to enhance TMZ resistance in glioblastoma [ 167 , 168 ].…”

“…Higher expression levels in glioblastoma tissues compared to normal tissues are associated with a poorer prognosis in high-risk patients. Additionally, HNRNPC expression positively correlates with PD-L1, highlighting its prognostic significance and role in immune modulation [ 166 ]. HNRNPC interacts with long non-coding RNA DDX11 antisense RNA 1 (DDX11-AS1) to promote the Wnt/β-Catenin and AKT pathways, influencing the epithelial–mesenchymal transition (EMT) and glioma cell migration.…”

m6A mRNA Modifications in Glioblastoma: Emerging Prognostic Biomarkers and Therapeutic Targets

“…Investigation of the participation of m 6 A regulators in glioblastoma and their connection with the tumor immune microenvironment (TIME) has been reported [46]. In a sentinel study, a comprehensive collection of potential m 6 A RNA regulators was acquired and an evaluation of PD-L1 and PD-1 levels, immune cell infiltration, and immune scores was conducted.…”