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. 2020 Mar 20;12(3):736. doi: 10.3390/cancers12030736

Table 1.

Functions of RNA-modifying proteins (RMPs) in GBM.

Gene Symbol Gene Description Role in RNA Modification Expression Biological Function Mechanism Reference
METTL3 Methyltransferase-like 3 m6A writer Elevated or decreased (controversial) Maintains or prevents stemness of GSSs; transforms or reverse malignancy; enhances radiosensitivity; reduces migration and induces apoptosis (controversial) Installs m6A marks in GSCs-specifically-expressed genes, such as SOX2; modulates ADAR1 and APOBEC3A to induce A-to I and C-to-U editing; upregulates BCL-X and NCOR2 to affect the levels of SRSFs; prevents YTHDC1-dependent NMD; introduces m6A modifications in critical factors, such as ADAM19; downregulates HSP70 expression [56,57,58,59,60]
METTL14 Methyltransferase-like 14 m6A writer Elevated or Decreased (controversial) Prevents growth, self-renewal, and tumorigenesis of GSCs Introduces m6A modifications in critical factors, such as ADAM19 [58,59]
WTAP Wilms’ tumor 1-associated protein m6A writer Elevated Stimulates tumorigecity, migration and invasion and inhibits apoptosis Increases EGFR expression; [58,61,62,63]
VIRMA/KIAA1429 Virilizer like m6A methyltransferase associated protein m6A writer Decreased - - [58]
ZC3H13/KIAA0853/Flacc Zinc finger CCCH domain-containing protein 13 m6A writer Decreased Inhibits malignant tansformation and reduces chemosensitivity - [58]
RBM15 RNA binding motif protein 15 m6A writer Elevated - - [58]
RBM15B RNA binding motif protein 15B m6A writer Elevated - - [58]
FTO Fat mass and obesity-associated protein m6A and m6Am eraser Decreased or elevated (controversial) Promotes self-renewal ability and tumorigenecity of GSCs Maintains the stability of c-Myc and CEBPA transcripts [58,59,64]
ALKBH5 α-Ketoglutarate-dependent dioxygenase alkB homolog 5 m6A eraser Elevated Inhibits cell proliferation of GSCs Demethylates FOXM1 nascent transcripts to enhance its expression by the aid of lncRNA FOXM1-AS [58,65]
YTHDF1 YTH N6-methyladenosine RNA binding protein 1 m6A reader Elevated - - [58]
YTHDF2 YTH N6-methyladenosine RNA binding protein 2 m6A reader Elevated - - [58]
YTHDF3 YTH N6-methyladenosine RNA binding protein 3 m6A reader Elevated - - [58]
YTHDC1 YTH domain-containing 1 m6A reader - Maintains stemness of GSCs - [57]
YTHDC2 YTH domain-containing 2 m6A reader Elevated in LGGs; decreased in GBM - - [58]
IGF2BP1/IMP1 Insulin like growth factor 2 mRNA binding protein 1 m6A reader Elevated Promotes cell proliferation and invasion Stabilizes the mRNA transcripts of its target genes, including c-Myc, MKI67, PTEN and CD44 [66,67].
IGF2BP2/IMP2 Insulin like growth factor 2 mRNA binding protein 2 m6A reader Elevated Promotes cell proliferation, migration, invasion and EMT; sensitizes GBM to TMZ treatment; maintains stemness of GSCs; promotes OXPHOS; promotes hypoxia-dependent molecular reprogramming Activates IGF2-mediated PI3K/AKT signaling; binds to let-7 MREs and prevents LIN28-independent let-7 target gene silencing, including HMGA1, HMGA2, CCND2 and RRM2; binds to several mRNAs such as COX7B, NDUS7, NDUF3 and NDUFS3; interacts with HIF1A-AS2 to maintain HMGA1 expression [68,69,70,71]
IGF2BP3/IMP3 Insulin like growth factor 2 mRNA binding protein 3 m6A reader Elevated Promotes cell proliferation, anchorage-independent growth, invasion, EMT and chemoresistance Activates PI3K/MAPK via promoting IGF2 translation; enhances translation of p65 (RELA)
eIF3b Eukaryotic translation initiation factor 3 subunit b m6A reader Dcreased Inhibits cell proliferation and induces G0/G1 cell cycle arrest and apoptosis - [72]
eIF3h Eukaryotic translation initiation factor 3 subunit h m6A reader Dublicated - - [73]
hnRNPA2B1 Heterogeneous nuclear ribonucleoprotein A2/B1 m6A reader Elevated Promotes GBM cell viability, adhesion, migration, invasion, chemoresistance to TMZ and tumorigenecity as well as protects cells from apoptosis and reactive oxygen species (ROS) generation Interacts with SOX2; downregulates tumor suppressors such as c-FLIP, BIN1 and WWOX, and upregulates phospho-STAT3, MMP-2, and the proto-oncogene RON [58,74,75]
hnRNPC Heterogeneous nuclear ribonucleoprotein C m6A reader Elevated in LGGs but decreased in GBM Promotes migratory and invasive activities, increases cell proliferation and protects GBM cells from etoposide-induced apoptosis Interacts with SOX2; binds directly to pri-mir-21 and promotes the processing of miR-21 that targets PDCD4, supporting Akt and p70S6K activation, [58,76]
METTL4 Methyltransferase-like 4 m6Am writer Missensely mutated - - [77]
DCP2 Decapping mRNA 2 m6Am reader Participates in radiosensitivity and DNA damage response - [78]
TRMT6/TRM6 tRNA methyltransferase 6 m1A writer Elevated - - [79]
TRMT61A/TRM61A tRNA methyltransferase 61A m1A writer Elevated - - [79]
ALKBH1 α-Ketoglutarate-dependent dioxygenase alkB homolog 1 m1A eraser Elevated Promotes cell proliferation and tumorigenecity Induces DNA demethylation on hypoxia response genes, [80]
NSUN5 NOP2/Sun RNA methyltransferase 5 m5C writer Decreased Leads to an adaptive translational program for survival under cellular stress and renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1 Drives an overall depletion of protein synthesis [81,82]
LYREF Aly/REF export factor m5C reader Elevated - - [83,84]
TET1 Tet methylcytosine dioxygenase 1 hm5C writer Elevated - - [85]
TET2 Tet methylcytosine dioxygenase 2 hm5C writer Decreased - - [86]
TET3 Tet methylcytosine dioxygenase 3 hm5C writer Decreased - - [87]
ADAR1/ADAR Adenosine deaminase RNA specific 1 I writer Decreased Inhibits cell proliferation Downregulates A-to-I RNA editing [88]
ADAR2/ADARB1 Adenosine deaminase RNA specific 2 I writer Decreased Inhibits cell proliferation Downregulates A-to-I RNA editing in the pre-mRNA of a phosphatase CDC14B, thereby downregulates Skp2/p21/p27 proteins [88,89,90]
ADAR3/ADARB2 Adenosine deaminase RNA specific 3 I writer Decreased - - [88]
DKC1 Dyskerin pseudouridine synthase 1 ψ writer Elevated Promotes cell growth by stimulating cell cycle progression and activates migration Upregulates N-cadherin, HIF1A, and MMP-2 expression [91]

Modification abbreviations: A-to-I, adenosine-to-inosine; C-to-U, cytidine to uridine, m1A, N1-methyladenosine; m5C, 5-methylcytosine; m6A, N6-methyladenosine; m6Am, N6, 2′O-dimethyladenosine; hm5C, 5-hydroxymethylcytosine; I, inosine; ψ, pseudouridine. Others: ADAM19, a disintegrin and metallopeptidase domain 19; ADAR1,adenosine deaminase RNA specific 1; APOBEC3A, apolipoprotein B mRNA editing enzyme catalytic subunit 3A; BCL-X, Bcl-2-like protein 1, BCL2L1; BIN1, bridging integrator 1; c-FLIP, cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein; c-Myc, avian myelocytomatosis viral oncogene homolog; CCND2, cyclin D2; CDC14B, cell division cycle 14B; CEBPA, CCAAT enhancer binding protein alpha; COX7B, mitochondrial cytochrome c oxidase subunit 7B; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; FOXM1, forkhead box M1; FOXM1-AS, forkhead box M1-antisense RNA; GBM, glioblastoma; GSCs, glioma stem-like cells; HIF1A, hypoxia-inducible factor 1 alpha; HIF1A-AS2, hypoxia-inducible factor 1 alpha-antisense RNA 2; HMGA1/2, high mobility group AT-hook 1/2; HSP70, heat shock protein 70; IGF2, insulin-like growth factor 2; LGG, low-grade glioma; MAPK, mitogen-activated protein kinase; MKI67, marker of proliferation Ki-67; MMP-2, matrix metallopeptidase 2; MRE, miRNA recognition element; NCOR2, nuclear receptor corepressor 2; NDUF3,NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3; NDUFS3, mitochondrial NADH dehydrogenase [ubiquinone] iron-sulfur protein 3; NDUS7, NADH dehydrogenase iron-sulfur protein 7; NMD, nonsense-mediated mRNA decay; NQO1, Quaking gene isoform 6; OXPHOS, oxidative phosphorylation; p70S6K, p70 S6 kinase; PDCD4, programmed cell death 4; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RON, macrophage stimulating 1 receptor, MST1R; RRM2, ribonucleotide reductase regulatory subunit M2; Skp2, S-phase kinase associated protein 2; SOX2, SRY-box transcription factor 2; STAT3, signal transducer and activator of transcription 3; TMZ, temozolomide; WWOX, WW domain containing oxidoreductase.