Abstract
N6-methyladenosine (m6A) RNA methylation, associated with cancer initiation and progression, is dynamically regulated by the m6A RNA methylation regulators (“writers”, “erasers” and “readers”). Here, we demonstrate that most of the thirteen main m6A RNA methylation regulators are differentially expressed among gliomas stratified by different clinicopathological features in 904 gliomas. We identified two subgroups of gliomas (RM1/2) by applying consensus clustering to m6A RNA methylation regulators. Compared with the RM1 subgroup, the RM2 subgroup correlates with a poorer prognosis, higher WHO grade, and lower frequency of IDH mutation. Moreover, the hallmarks of epithelial-mesenchymal transition and TNFα signaling via NF-κB are also significantly enriched in the RM2 subgroup. This finding indicates that m6A RNA methylation regulators are closely associated with glioma malignancy. Based on this finding, we derived a risk signature, using seven m6A RNA methylation regulators, that is not only an independent prognostic marker but can also predict the clinicopathological features of gliomas. Moreover, m6A regulators are associated with the mesenchymal subtype and TMZ sensitivity in GBM. In conclusion, m6A RNA methylation regulators are crucial participants in the malignant progression of gliomas and are potentially useful for prognostic stratification and treatment strategy development.
Highlights
In the traditional concept, epigenetics only involves the reversible chemical modification of DNA or proteins and regulates gene expression independent of DNA sequences, which could be heritable through cell division [1]
The significant correlations between WHO grades and expression levels of WT1associated protein (WTAP), RNA binding motif protein 15 (RBM15), YTHDF, ALBKH5, and fat mass- and obesityassociated protein (FTO) were confirmed by quantitative analyses in both the Chinese Glioma Genome Atlas (CGGA) (Fig. 1C) and The Cancer Genome Atlas (TCGA) datasets (Fig. 1D)
We studied the relationship between IDH status and expression levels of each m6A RNA methylation regulator in lower-grade gliomas (LGG, Fig. 1E and 1F) and glioblastomas (GBM, Fig. 1G), respectively
Summary
Epigenetics only involves the reversible chemical modification of DNA or proteins (histones) and regulates gene expression independent of DNA sequences, which could be heritable through cell division [1]. RNA modification has been identified in almost all forms of native cellular RNA, including mRNAs, tRNAs, rRNAs, small nuclear RNAs, small nucleolar RNAs, long noncoding RNAs (lncRNAs) and micro-RNAs (miRNA) [5,6,7,8,9,10,11,12]. It has been reported in several forms, including N1-methyladenosine, N7methyladenosine, 5-methylcytosine, pseudouridine, N6,2’-O-dimethyladenosine (m6A) and 2′-O-methylation [5, 11, 13]. The discovery of m6A RNA methylation regulators has dramatically increased our understanding of the function and mechanism of m6A modification in the posttranscriptional regulation of gene expression [6, 12, 15, 22, 23]
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