Abstract
N6-methyladenosine (m6A) RNA methylation, the most common form of mRNA modification and regulated by the m6A RNA methylation regulators (“writers,” “erasers,” and “readers”), has been reported to be associated with the progression of the malignant tumor. However, its role in glioblastoma (GBM) has been poorly known. This study aimed to identify the expression, potential functions, and prognostic values of m6A RNA methylation regulators in GBM. Here, we revealed that the 13 central m6A RNA methylation regulators were firmly related to the clinical and molecular phenotype of GBM. Taking advantage of consensus cluster analysis, we obtained two categories of GBM samples and found malignancy-related processes of m6A methylation regulators and compounds that specifically targeted the malignant processes. Besides, we also obtained a list of genes with poor prognosis in GBM. Finally, we derived a risk-gene signature with three selected m6A RNA methylation regulators, which allowed us to extend the in-depth study and dichotomized the OS of patients with GBM into high- and low-risk subgroups. Notably, this risk-gene signature could be used as independent prognostic markers and accurate clinicopathological parameter predictors. In conclusion, m6A RNA methylation regulators are a type of vital participant in the malignant progression of GBM, with a critical potential in the prognostic stratification and treatment strategies of GBM.
Highlights
Given the critical role of epigenetic regulation of DNA and histone methylation in the underlying biological processes of mammals, the methyladenosine chemical modification of RNA may be used as an novel epigenetic marker of far-reaching biological significance [1, 2]
The significant correlation between the occurrence of GBM and the expression levels of alkB homolog 5 (ALKBH5), METTL3, KIAA1429, HNRNPC, WATP, YTHDC2, YTHDF1, YTHDF2, and fat mass and obesity-associated protein (FTO) were confirmed by the quantitative analysis of Chinese Glioma Genome Atlas (CGGA) (Figure 1B)
The expression of WT1associated protein (WTAP), ALKBH5, and methyltransferase like 14 (METTL14) was significantly associated with the recurrence of GBM. These results suggested that WTAP, ALKBH5, and METTL14 were firmly related to the recurrence process of GBM (Figures 1G,H)
Summary
Given the critical role of epigenetic regulation of DNA and histone (proteins) methylation in the underlying biological processes of mammals, the methyladenosine (mA) chemical modification of RNA may be used as an novel epigenetic marker of far-reaching biological significance [1, 2]. The m6A marks on mRNAs, similar to DNA and protein modification, are reversibly and dynamically regulated by methyltransferases (“writers”), binding proteins (“readers”), and demethylases (“erasers”). M6A Methylation Regulators in Glioblastoma (METTL3) [6], methyltransferase like 14 (METTL14) [7], WT1associated protein (WTAP) [8], RNA-binding motif protein 15/15B (RBM15/15B) [9], Vir like m6A methyltransferase associated VIRMA ( named as KIAA1429) [10], and zinc finger CCCH domain-containing protein 13 (ZC3H13) [11], which can catalyze the formation of m6A. As a function to decode m6A methylation and produce functional signals, the “readers” include YT521-B homology (YTH) domain-containing proteins (YTHDC1, YTHDC2) [12], YTH N6-methyladenosine RNAbinding proteins (YTHDF1, YTHDF2) [13], and heterogeneous nuclear ribonucleoprotein (HNRNP) protein families [14]. “Erasers” are capable of removing the methyl code from target mRNAs, including fat mass and obesity-associated protein (FTO) [15, 16] and alkB homolog 5 (ALKBH5) [17]
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