# The Emerging Roles of RNA Modifications in Glioblastoma
## 3 RNA Modifications in GBM
### RNA m\({}^{6}\)A Modification in GBM
#### 3.1.3 RNA m\({}^{6}\)A Readers in GBM  
The fate of m\({}^{6}\)A-modified RNA is determined by m\({}^{6}\)A readers, so they may be more important factors for cancer treatment, because when functions of m\({}^{6}\)A writers and erasers are settled, the functions of readers depend on what kinds of readers to carry out the effects of m\({}^{6}\)A marks. Importantly, the aberrant expression of m\({}^{6}\)A readers may contribute to GBM tumorigenesis independently of m\({}^{6}\)A alterations to some extent. This means that even in the condition that m\({}^{6}\)A is not changed, the effect of m\({}^{6}\)A may be altered by the abnormal expression of m\({}^{6}\)A readers. Based on current study, several families that exert as m\({}^{6}\)A readers are tightly related to the tumorigenesis of GBM. YTHDF and YTHDC families are the most important m\({}^{6}\)A readers that contain an YTH domain that can bind to RNAs. They exhibit different functions: YTHDC1 mediates mRNA splicing; YTHDF2, YTHDF3, and YTHDC2 mediate mRNA decay; YTHDF1, YTHDF3, and YTHDC2 mediate translation; and YTHDC2 mediates RNA structures [22]. YTHDC1 reads the m\({}^{6}\)A marks dependent on its tryptophan 377 (W377) or W428 sites [95]. Recently, these readers were shown to also participate in tumorigenesis of GBM. For instance, YTHDC1 deficiency reduces sphere number substantially in METTL3 overexpressed U87 cells but not in control cells. Overexpression W377A/W428A mutant YTHDC1 cannot promotes the sphere formation capacity of U87 cells, suggesting that YTHDC1 promotes GBM phenotype dependently on its m\({}^{6}\)A binding activity [57]. IGF2 BP Family  
Another m\({}^{6}\)A reader protein family, the IGF2 BP family, including IGF2 BP1/2/3, inhibits the degradation of m\({}^{6}\)A-modified transcripts and facilitates their translation [96]. For a long time, these factors are recognized as important regulators in GBM progression, even though there are no direct connections between their functions in m\({}^{6}\)A readers and oncogenic roles in GBM. For example, IGF2 BP1 promotes cell proliferation and invasion in GBM cells through stabilizing the mRNA transcripts of its target genes, including c-Myc, marker of proliferation Ki-67 (MKI67), phosphatase and tensin homolog (PTEN) and CD44 [66; 67]. However, whether this phenomenon depens on its activity in m\({}^{6}\)A reading remains unknown. IGF2 BP2 is also upregulated in GBM tissues. It supports GBM cell proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) via regulating the activity of insulin-like growth factor 2 (IGF2), which further activates phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Additionally, inhibition of IGF2 BP2 sensitizes GBM to TMZ treatment [68]. Another study shows that IGF2 BP2 binds to let-7 miRNA recognition elements (MREs) and prevents LIN28-independent let-7 target gene silencing, including high mobility group AT-hook 1 (HMGA1), HMGA2, cyclin D2 (CCND2) and ribonucleotide reductase regulatory subunit M2 (RRM2), thereby ensuring maintenance of stemness in GSCs [69]. In this process, IGF2 BP2 is responsible for miRNA maturation. IGF2 BP2 also interacts with lncRNAs such as hypoxia-inducible factor 1 \(\alpha\)-antisense RNA 2 (HIF1A-AS2), which functions as a subtype-specific hypoxia-inducible lncRNA, thereby maintaining the expression of their target gene, HMGA1, resulting in promoted GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming [71]. In addition, IGF2 BP2 also interacts with mRNAs and even proteins. For example, it can promote oxidative phosphorylation (OXPHOS) in primary GBM sphere cultures (gliomaspheres, GSCs) via binding several mRNAs such as mitochondrial cytochrome c oxidase subunit 7B (COX7B), NADH dehydrogenase iron-sulfur protein 7 (NDUS7), NADH dehydrogenase [ubiquinone] 1\(\alpha\) subcomplex assembly factor 3 (NDUF3) and mitochondrial NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3), that encode mitochondrial respiratory chain complex subunits.