The Emerging Roles of RNA Modifications in Glioblastoma

Abstract

Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation Sequencing (NGS) technology, more than 170 kinds of covalent ribonucleic acid (RNA) modifications are found to be extensively present in almost all living organisms and all kinds of RNAs, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and messenger RNAs (mRNAs). RNA modifications are also emerging as important modulators in the regulation of biological processes and pathological progression, and study of the epi-transcriptome has been a new area for researchers to explore their connections with the initiation and progression of cancers. Recently, RNA modifications, especially m6A, and their RNA-modifying proteins (RMPs) such as methyltransferase like 3 (METTL3) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), have also emerged as important epigenetic mechanisms for the aggressiveness and malignancy of GBM, especially the pluripotency of glioma stem-like cells (GSCs). Although the current study is just the tip of an iceberg, these new evidences will provide new insights for possible GBM treatments. In this review, we summarize the recent studies about RNA modifications, such as N6-methyladenosine (m6A), N6,2′O-dimethyladenosine (m6Am), 5-methylcytosine (m5C), N1-methyladenosine (m1A), inosine (I) and pseudouridine (ψ) as well as the corresponding RMPs including the writers, erasers and readers that participate in the tumorigenesis and development of GBM, so as to provide some clues for GBM treatment.

From m⁶A to Cap-Adjacent m⁶Am and Their Effects on mRNAs

“…The TMG cap is found on snRNAs, snoRNAs and certain other ncRNAs [80]. m 1 A modification is found mainly in tRNAs, mRNAs, long non-coding RNAs (lncRNAs), and mitochondrial genes [24]. In 2017, m 1 A was mapped near the transcription start sites (TSS) and the first splice site in coding sequences and shown to increase translation efficiency through enabling the non-canonical binding of the exon-exon junction complex at the 5' untranslated region (UTR) [83].…”

“…In addition, the methyl group of m 1 A is known to block Watson-Crick base pairing and effectively terminates reverse transcription and disrupts translation [83]. Similar to m 1 A, m 5 C sites are mapped in human mRNA and lncRNA species, however, m 5 C sites are mainly enriched in the 5' UTRs before translation initiation sites, and in close proximity to the translation stop codon [7,24,84]. Changes in the level of NSUN2, a key m 5 C methyl-transferase have been shown to strongly affect RNA metabolism; and are linked to various human neurodegenerative diseases and cancers [24,[85][86][87][88].…”

“…Numerous studies showed that mammalian m 6 A modifications are highly regulated and has profound effects on the cellular heat-shock response, stem cell proliferation and differentiation, the DNA damage response, and tumorigenesis [11,24,87,117,120,143,[153][154][155]. The first evidence of m 6 A causing mRNA instability was obtained using radioisotope metabolic labelling [29].…”

“…As tRNAs, snRNAs, snoRNAs, and rRNAs are both abundant and heavily (and specifically) modified in cells, RNA modifications were always of great interest in these fields [7,22,23]. In fact, the proper modification of key nucleotides is critical to the functions of many of these non-coding RNAs (ncRNA) [5,7,24,25].…”

Alpha-ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling

“…We first investigated AKG's effects on RNA m6A modification (N6-methyladenosine), which is the most prevalent RNA modification and has been reported in numerous human diseases, including several cancers 35,36 . In primary hepatocyte cell, we tested the AKG's effects on the mRNA expression of three major types of enzymes involved in m6A methylation: writers, erasers, and readers 35,37,38 . We found AKG failed to affect the mRNA expression of these writers, readers, and erasers ( Fig.…”