Abstract
m6A RNA methylation regulators can regulate the growth, progression, and invasion of glioma cells by regulating their target genes, which provides a reliable support for the m6A regulator–target axes as the novel therapeutic targets and clinical prognostic signature in glioma. This study aimed to explore the role and prognostic value of m6A RNA methylation regulators and their targets. Expression profiles and clinicopathological data were obtained from the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteome Tumor Analysis Consortium (CPTAC) datasets. Differential expression and correlation analyses were performed between normal and glioma tissues at mRNA and protein levels. Univariate Cox regression, survival, and Lasso Cox regression analyses were conducted to identify and establish the prognostic gene signature. Kaplan–Meier curve, multivariate Cox regression analysis, and ROC were utilized to evaluate the prognostic capacity of the prognostic gene signature. The correlation analysis, systematic bioinformatics analysis, and cell experiment were performed to further understand the potential underlying molecular mechanisms and drug sensitivity. Our results suggested that IGF2BP2, KIAA1429, METTL16, and METTL3, as well as 208 targets are involved in the occurrence of glioma, GBM, and LGG. YTHDF1 and 78 targets involved the occurrence of glioma and GBM, not LGG, among which 181 genes were associated with overall survival. From other findings and our cell experiment results, we demonstrated that METTL3 can activate Notch pathway and facilitate glioma occurrence through regulating its direct targets NOTCH3, DLL3, and HES1, and Notch pathway genes may serve as the potential treatment targets for glioma. Our study established and validated a seven-gene signature comprising METTL3, COL18A1, NASP, PHLPP2, TIMP1, U2AF2, and VEGFA, with a good capability for predicting glioma survival, which may guide therapeutic customization and clinical decision-making. These genes were identified to influence 81 anticancer drug responses, which further contributes to the early phase clinical trials of drug development.
Highlights
N6-methyladenosine (m6A) RNA methylation, first discovered in the 1970s, is the most prevalent dynamic and reversible epigenetic modification in mRNAs (Desrosiers et al, 1974). m6A RNA methylation on target gene is installed by methyltransferases containing Methyltransferase-Like 3 (METTL3), METTL14, WTAP, Methyltransferase-Like 16 (METTL16), ZCCHC4, and KIAA1429, among others, and removed by demethylases composed of FTO and ALKBH5
We found that IGF2BP2, KIAA1429, METTL16, METTL3, and YTH N6Methyladenosine RNA Binding Protein 1 (YTHDF1) are consistently upregulated at the mRNA level of Chinese Glioma Genome Atlas (CGGA) and GSE16011 datasets (7.97E-05 < false discovery rate (FDR) < 0.04) (Figures 1B,C and Supplementary Table S3)
In two CGGA mRNA datasets, we found that glioma patients with high expressions of METTL3, IGF2BP2, Vascular Endothelial Growth Factor A (VEGFA), TIMP Metallopeptidase Inhibitor 1 (TIMP1), Hes Family BHLH Transcription Factor 1 (HES1), Collagen Type XVIII Alpha Chain (COL18A1), TK1, DNAJB11, CENPK, Nuclear Autoantigenic Sperm Protein (NASP), and U2 Small Nuclear RNA Auxiliary Factor 2 (U2AF2) have a shorter overall survival (HR > 1, p < 0.05) (Figure 5A and Supplementary Table S8), while those with high expressions of PHLPP2, ATP6V1A, and Delta-Like Canonical Notch Ligand 3 (DLL3) show a good overall survival (HR < 1, p < 0.05) (Figure 5B and Supplementary Table S8)
Summary
N6-methyladenosine (m6A) RNA methylation, first discovered in the 1970s, is the most prevalent dynamic and reversible epigenetic modification in mRNAs (Desrosiers et al, 1974). m6A RNA methylation on target gene is installed by methyltransferases (writers) containing METTL3, METTL14, WTAP, METTL16, ZCCHC4, and KIAA1429, among others, and removed by demethylases (erasers) composed of FTO and ALKBH5. The function of m6A-modified targets is executed by m6A binding proteins (readers) through binding to m6A directly or indirectly, including YTH N6-methyladenosine RNA-binding proteins, YTH domain-containing proteins, IGF2BPs, and HNRNP protein families (Tong et al, 2018) These writers, erasers, and readers, serving as m6A RNA methylation regulators, can influence mRNA of target gene at different levels, including nuclear export, translation, splicing, stability, and decay (Lan et al, 2019; Huang et al, 2020; Nombela et al, 2021) and have important influences in diverse physiological and pathological processes, such as cell proliferation and differentiation, oncogenic protein expression, and the proliferation, survival, initiation, and progression of tumor cell (Figure 1A; Chen et al, 2019; Lan et al, 2019; Du et al, 2020; Huang et al, 2020; Nombela et al, 2021). Strong evidence suggested that m6A RNA methylation regulators including METTL3, METTL14, FTO, and YTHDF2 can regulate the self-renewal, tumorigenesis, growth and progression, and invasion of glioma cell by altering mRNA expression levels of their target genes (e.g., ADAM19, MYC, VEGFA, NCOR2, and HIVEP2) (Cui et al, 2017; Li F. et al, 2019; Dixit et al, 2021; Fang et al, 2021; Huff et al, 2021), which provides a reliable support for the m6A RNA methylation regulator–target gene axes as specific and novel therapeutic targets and clinical prognostic biomarkers in glioma
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