Skip to main content

Advertisement

SpringerLink
Log in

The Critical Role of RNA m6A Methylation in Gliomas: Targeting the Hallmarks of Cancer

  • Review Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Gliomas are the most common central cancer with high aggressive-capacity and poor prognosis, remaining to be the threat of most patients. With the blood–brain barrier and highly malignant progression, the efficacy of high-intensity treatment is limited. The N6-methyladenine (m6A) modification is found in rRNA, snRNA, miRNA, lncRNA, and mRNA, influencing the metabolism and translation of these RNAs and consequently regulating the proliferation, metastasis, apoptosis, etc. of glioma cells. The key role that m6A modification in gliomas has played makes it a prospective target for diagnosis and treatment. However, with studying deeper in m6A modification and gliomas, the conclusion and mechanism are abundant and complex. This review focused on the dysregulation of m6A regulators and m6A modification of key genes and pathways in Hallmarks of gliomas. Furthermore, the potential of exploiting m6A modification for gliomas diagnosis and therapeutics was also discussed. This review will summarize the recent studies about m6A modification, revealing that m6A modification plays an important role in the malignant progression, angiogenesis, microenvironment, and genome instability in gliomas by exploring the interaction and network between m6A modification-related regulators and classical tumor-related genes. And it might provide some clue for the molecular mechanism, diagnosis, and treatment of gliomas.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

References

  • Ahir BK, Engelhard HH, Lakka SS (2020) Tumor development and angiogenesis in adult brain tumor: Glioblastoma. Mol Neurobiol 57:2461–2478

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF (2015) HNRNPA2B1 is a mediator of m6A-dependent nuclear RNA processing events. Cell 162:1299–1308

    PubMed  PubMed Central  Google Scholar 

  • Annibali D, Whitfield JR, Favuzzi E, Jauset T, Serrano E, Cuartas I, Redondo-Campos S, Folch G, Gonzàlez-Juncà A, Sodir NM (2014) Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis. Nat Commun 5:1–11

    Google Scholar 

  • Atkinson GP, Nozell SE, Benveniste EN (2010) NF-κB and STAT3 signaling in glioma: targets for future therapies. Expert Rev Neurother 10:575–586

    CAS  PubMed  Google Scholar 

  • Balacco DL, Soller M (2018) The m6A writer: rise of a machine for growing tasks. Biochemistry 58:363–378

    PubMed  Google Scholar 

  • Bhargava S, Visvanathan A, Patil V, Kumar A, Kesari S, Das S, Hegde AS, Arivazhagan A, Santosh V, Somasundaram K (2017) IGF2 mRNA binding protein 3 (IMP3) promotes glioma cell migration by enhancing the translation of RELA/p65. Oncotarget 8:40469

    PubMed  PubMed Central  Google Scholar 

  • Boccaletto P, Stefaniak F, Ray A, Cappannini A, Mukherjee S, Purta E, Kurkowska M, Shirvanizadeh N, Destefanis E, Groza P (2022) MODOMICS: a database of RNA modification pathways. 2021 update. Nucl Acids Res 50:D231–D235

    CAS  PubMed  Google Scholar 

  • Cao Y, Zhu H, Liu W, Wang L, Yin W, Tan J, Zhou Q, Xin Z, Huang H, Xie D (2021) Multi-omics analysis based on genomic instability for prognostic prediction in lower-grade glioma. Front Genet. https://doi.org/10.3389/fgene.2021.758596

    Article  PubMed  PubMed Central  Google Scholar 

  • Castosa R, Martinez-Iglesias O, Roca-Lema D, Casas-Pais A, Díaz-Díaz A, Iglesias P, Santamarina I, Graña B, Calvo L, Valladares-Ayerbes M (2018) Hakai overexpression effectively induces tumour progression and metastasis in vivo. Sci Rep 8:1–10

    CAS  Google Scholar 

  • Chai R-C, Chang Y-Z, Chang X, Pang B, An SY, Zhang K-N, Chang Y-H, Jiang T, Wang Y-Z (2021) YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-κB and promote the malignant progression of glioma. J Hematol Oncol 14:1–16

    Google Scholar 

  • Cheng CK, Fan QW, Weiss WA (2009) PI3K signaling in glioma—animal models and therapeutic challenges. Brain Pathol 19:112–120

    CAS  PubMed  Google Scholar 

  • Choi YC, Busch H (1978) Modified nucleotides in T1 RNase oligonucleotides of 18S ribosomal RNA of the Novikoff hepatoma. Biochemistry 17:2551–2560

    CAS  PubMed  Google Scholar 

  • Chokkalla AK, Mehta SL, Vemuganti R (2020) Epitranscriptomic regulation by m6A RNA methylation in brain development and diseases. J Cereb Blood Flow Metab 40:2331–2349

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cohen AL, Colman H (2015) Glioma Biology and Molecular Markers In Current Understanding and Treatment of Gliomas. Springer International Publishing, Cham

    Google Scholar 

  • Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, Sun G, Lu Z, Huang Y, Yang C, Riggs A, He C, Shi Y (2017) mA RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep 18:2622–2634. https://doi.org/10.1016/j.celrep.2017.02.059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Degrauwe N, Schlumpf TB, Janiszewska M, Martin P, Cauderay A, Provero P, Riggi N, Suva M-L, Paro R, Stamenkovic I (2016) The RNA binding protein IMP2 preserves glioblastoma stem cells by preventing let-7 target gene silencing. Cell Rep 15:1634–1647

    CAS  PubMed  Google Scholar 

  • Deng J, Chen S, Wang F, Zhao H, Xie Z, Xu Z, Zhang Q, Liang P, Zhai X, Cheng Y (2016) Effects of hnRNP A2/B1 knockdown on inhibition of glioblastoma cell invasion, growth and survival. Mol Neurobiol 53:1132–1144

    CAS  PubMed  Google Scholar 

  • Deng X, Su R, Weng H, Huang H, Li Z, Chen J (2018) RNA N6-methyladenosine modification in cancers: current status and perspectives. Cell Res 28:507–517

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q, Qiu Z, Kidwell RL, Kim LJ, Xie Q (2021) The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells. Cancer Discov 11:480–499

    CAS  PubMed  Google Scholar 

  • Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485:201–206

    CAS  PubMed  Google Scholar 

  • Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G (2013) Transcriptome-wide mapping of N 6-methyladenosine by m 6 A-seq based on immunocapturing and massively parallel sequencing. Nat Protoc 8:176–189

    CAS  PubMed  Google Scholar 

  • Dong Z, Cui H (2020) The emerging roles of RNA modifications in glioblastoma. Cancers. https://doi.org/10.3390/cancers12030736

    Article  PubMed  PubMed Central  Google Scholar 

  • Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, Ma J, Wu L (2016) YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex. Nat Commun 7:1–11

    Google Scholar 

  • Ensfelder TT, Kurz MQ, Iwan K, Geiger S, Matheisl S, Müller M, Beckmann R, Carell T (2018) ALKBH5-induced demethylation of mono-and dimethylated adenosine. Chem Commun 54:8591–8593

    CAS  Google Scholar 

  • Fang R, Chen X, Zhang S, Shi H, Ye Y, Shi H, Zou Z, Li P, Guo Q, Ma L (2021) EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. Nat Commun 12:1–17

    Google Scholar 

  • Figueroa A, Fujita Y, Gorospe M (2009) Hacking RNA: Hakai promotes tumorigenesis by enhancing the RNA-binding function of PSF. Cell Cycle 8:3648–3651

    CAS  PubMed  Google Scholar 

  • Fujita Y, Krause G, Scheffner M, Zechner D, Leddy HEM, Behrens J, Sommer T, Birchmeier W (2002) Hakai, a c-Cbl-like protein, ubiquitinates and induces endocytosis of the E-cadherin complex. Nat Cell Biol 4:222–231

    CAS  PubMed  Google Scholar 

  • Golan-Gerstl R, Cohen M, Shilo A, Suh S, Bakàcs A, Coppola L, Karni R (2011) Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma. Can Res 71:4464–4472. https://doi.org/10.1158/0008-5472.Can-10-4410

    Article  CAS  Google Scholar 

  • Gong A, Huang S (2012) FoxM1 and Wnt/β-catenin signaling in glioma stem cells. Can Res 72:5658–5662

    CAS  Google Scholar 

  • Guo F, Deng T, Shi L, Wu P, Yan J, Ling G, Chen H, Huang Q, Mu J, Mo L (2022) Identification of an m6A RNA methylation regulator risk score model for prediction of clinical prognosis in astrocytoma. Comput Math Methods Med. https://doi.org/10.1155/2022/7168929

    Article  PubMed  PubMed Central  Google Scholar 

  • Gutmann D, Kettenmann H (2019) Microglia/brain macrophages as central drivers of brain tumor pathobiology. Neuron 104:442–449. https://doi.org/10.1016/j.neuron.2019.08.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanahan D (2022) Hallmarks of cancer: new dimensions. Cancer Discov 12:31–46. https://doi.org/10.1158/2159-8290.Cd-21-1059

    Article  CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    CAS  PubMed  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    CAS  PubMed  Google Scholar 

  • Harper JE, Miceli SM, Roberts RJ, Manley JL (1990) Sequence specificity of the human mRNA N6-adenosine methylase in vitro. Nucleic Acids Res 18:5735–5741

    CAS  PubMed  PubMed Central  Google Scholar 

  • Horiuchi K, Kawamura T, Iwanari H, Ohashi R, Naito M, Kodama T, Hamakubo T (2013) Identification of Wilms’ tumor 1-associating protein complex and its role in alternative splicing and the cell cycle. J Biol Chem 288:33292–33302

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, Zhao BS, Mesquita A, Liu C, Yuan CL (2018) Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 20:285–295

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang T, Song X, Xu D, Tiek D, Goenka A, Wu B, Sastry N, Hu B, Cheng S-Y (2020) Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics 10:8721

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huff S, Tiwari SK, Gonzalez GM, Wang Y, Rana TM (2021) m6A-RNA demethylase FTO inhibitors impair self-renewal in glioblastoma stem cells. ACS Chem Biol 16:324–333

    CAS  PubMed  PubMed Central  Google Scholar 

  • Janiszewska M, Suvà ML, Riggi N, Houtkooper RH, Auwerx J, Clément-Schatlo V, Radovanovic I, Rheinbay E, Provero P, Stamenkovic I (2012) Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev 26:1926–1944

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ji J, Zhang Y, Lai Y, Huang C (2020) Mettl3 regulates the proliferation, migration and invasion of glioma cells by inhibiting PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci 24:3818–3828

    PubMed  Google Scholar 

  • Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, Yi C, Lindahl T, Pan T, Yang Y, He C (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7:885–887. https://doi.org/10.1038/nchembio.687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin DI, Lee SW, Han ME, Kim HJ, Seo SA, Hur GY, Jung S, Kim BS, Oh SO (2012) Expression and roles of W ilms’ tumor 1-associating protein in glioblastoma. Cancer Sci 103:2102–2109

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson H, Del Rosario AM, Bryson BD, Schroeder MA, Sarkaria JN, White FM (2012) Molecular characterization of EGFR and EGFRvIII signaling networks in human glioblastoma tumor xenografts. Mol Cell Proteomics 11:1724–1740

    PubMed  PubMed Central  Google Scholar 

  • Kan LK, Drummond K, Hunn M, Williams D, O’Brien TJ, Monif M (2020) Potential biomarkers and challenges in glioma diagnosis, therapy and prognosis. BMJ Neurol Open. https://doi.org/10.1136/bmjno-2020-000069

    Article  PubMed  PubMed Central  Google Scholar 

  • Lence T, Akhtar J, Bayer M, Schmid K, Spindler L, Ho CH, Kreim N, Andrade-Navarro MA, Poeck B, Helm M (2016) m6A modulates neuronal functions and sex determination in drosophila. Nature 540:242–247

    CAS  PubMed  Google Scholar 

  • Lence T, Paolantoni C, Worpenberg L, Roignant J-Y (2019) Mechanistic insights into m6A RNA enzymes. Biochim Biophys Acta 1862:222–229

    CAS  Google Scholar 

  • Li L, Yang Y, Wu M, Yu Z, Wang C, Dou G, He H, Wang H, Yang N, Qi H (2018) β-Asarone induces apoptosis and cell cycle arrest of human glioma U251 cells via suppression of HnRNP A2/B1-mediated pathway in vitro and in vivo. Molecules 23:1072

    PubMed  PubMed Central  Google Scholar 

  • Li F, Yi Y, Miao Y, Long W, Long T, Chen S, Cheng W, Zou C, Zheng Y, Wu X (2019a) N6-methyladenosine modulates nonsense-mediated mRNA decay in human glioblastoma. Can Res 79:5785–5798

    CAS  Google Scholar 

  • Li F, Zhang C, Zhang G (2019b) m6A RNA methylation controls proliferation of human glioma cells by influencing cell apoptosis. Cytogenet Genome Res 159:119–125

    CAS  PubMed  Google Scholar 

  • Li H, Di Wang BY, Cai H, Wang Y, Lou X, Xi Z, Li Z (2021a) SUMOylation of IGF2BP2 promotes vasculogenic mimicry of glioma via regulating OIP5-AS1/miR-495-3p axis. Int J Biol Sci 17:2912

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li XD, Wang MJ, Zheng JL, Wu YH, Wang X, Jiang XB (2021b) Long noncoding RNA just proximal to X-inactive specific transcript facilitates aerobic glycolysis and temozolomide chemoresistance by promoting stability of PDK1 mRNA in an m6A-dependent manner in glioblastoma multiforme cells. Cancer Sci 112:4543

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T (2015) N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions. Nature 518:560–564

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu N, Zhou K, Parisien M, Dai Q, Diatchenko L, Pan T (2017) N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res 45:6051–6063. https://doi.org/10.1093/nar/gkx141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu B, Zhou J, Wang C, Chi Y, Wei Q, Fu Z, Lian C, Huang Q, Liao C, Yang Z (2020a) LncRNA SOX2OT promotes temozolomide resistance by elevating SOX2 expression via ALKBH5-mediated epigenetic regulation in glioblastoma. Cell Death Dis 11:1–18

    CAS  Google Scholar 

  • Liu X, Wu P, Su R, Xue Y, Yang C, Wang D, Ruan X, Zheng J, Yang Y, Li Z (2020b) IGF2BP2 stabilized FBXL19-AS1 regulates the blood-tumour barrier permeability by negatively regulating ZNF765 by STAU1-mediated mRNA decay. RNA Biol 17:1777–1788

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H, Qin S, Liu C, Jiang L, Li C, Yang J, Zhang S, Yan Z, Liu X, Yang J (2021a) m6A reader IGF2BP2-stabilized CASC9 accelerates glioblastoma aerobic glycolysis by enhancing HK2 mRNA stability. Cell Death Discov 7:1–8

    Google Scholar 

  • Liu Z, Chen Y, Wang L, Ji S (2021b) ALKBH5 promotes the proliferation of glioma cells via enhancing the mRNA stability of G6PD. Neurochem Res 46:3003–3011

    CAS  PubMed  Google Scholar 

  • Llaguno SA, Chen J, Kwon C-H, Jackson EL, Li Y, Burns DK, Alvarez-Buylla A, Parada LF (2009) Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15:45–56

    CAS  Google Scholar 

  • Mangelberger D, Kern D, Loipetzberger A, Eberl M, Aberger F (2012) Cooperative hedgehog-egfr signaling. Front Biosci. https://doi.org/10.2741/3917

    Article  Google Scholar 

  • Mauer J, Luo X, Blanjoie A, Jiao X, Grozhik AV, Patil DP, Linder B, Pickering BF, Vasseur J-J, Chen Q (2017) Reversible methylation of m6Am in the 5′ cap controls mRNA stability. Nature 541:371–375

    CAS  PubMed  Google Scholar 

  • Mauer J, Sindelar M, Despic V, Guez T, Hawley B, Vasseur J, Rentmeister A, Gross S, Pellizzoni L, Debart F, Goodarzi H, Jaffrey S (2019) FTO controls reversible mAm RNA methylation during snRNA biogenesis. Nat Chem Biol 15:340–347. https://doi.org/10.1038/s41589-019-0231-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meel MH, Schaper SA, Kaspers GJ, Hulleman E (2018) Signaling pathways and mesenchymal transition in pediatric high-grade glioma. Cell Mol Life Sci 75:871–887

    CAS  PubMed  Google Scholar 

  • Miao Y-Q, Chen W, Zhou J, Shen Q, Sun Y, Li T, Wang S-C (2022) N (6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner. Bioengineered 13:1858–1871

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mineo M, Ricklefs F, Rooj AK, Lyons SM, Ivanov P, Ansari KI, Nakano I, Chiocca EA, Godlewski J, Bronisz A (2016) The long non-coding RNA HIF1A-AS2 facilitates the maintenance of mesenchymal glioblastoma stem-like cells in hypoxic niches. Cell Rep 15:2500–2509

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mu Q, Wang L, Yu F, Gao H, Lei T, Li P, Liu P, Zheng X, Hu X, Chen Y (2015) Imp2 regulates GBM progression by activating IGF2/PI3K/Akt pathway. Cancer Biol Ther 16:623–633

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nayler O, Hartmann AM, Stamm S (2000) The ER repeat protein YT521-B localizes to a novel subnuclear compartment. J Cell Biol 150:949–962

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oerum S, Meynier V, Catala M, Tisné C (2021) A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res 49:7239–7255

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pan Z, Zhao R, Li B, Qi Y, Qiu W, Guo Q, Zhang S, Zhao S, Xu H, Li M, Gao Z, Fan Y, Xu J, Wang H, Wang S, Qiu J, Wang Q, Guo X, Deng L, Zhang P, Xue H, Li G (2022) EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3. Mol Cancer 21:16. https://doi.org/10.1186/s12943-021-01485-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park YM, Hwang SJ, Masuda K, Choi K-M, Jeong M-R, Nam D-H, Gorospe M, Kim HH (2012) Heterogeneous nuclear ribonucleoprotein C1/C2 controls the metastatic potential of glioblastoma by regulating PDCD4. Mol Cell Biol 32:4237–4244

    CAS  PubMed  PubMed Central  Google Scholar 

  • Patil DP, Chen C-K, Pickering BF, Chow A, Jackson C, Guttman M, Jaffrey SR (2016) m6A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537:369–373

    CAS  PubMed  PubMed Central  Google Scholar 

  • Penn JK, Graham P, Deshpande G, Calhoun G, Chaouki AS, Salz HK, Schedl P (2008) Functioning of the drosophila wilms’-tumor-1-associated protein homolog, Fl (2) d, in sex-lethal-dependent alternative splicing. Genetics 178:737–748

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ping X-L, Sun B-F, Wang L, Xiao W, Yang X, Wang W-J, Adhikari S, Shi Y, Lv Y, Chen Y-S (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24:177–189

    CAS  PubMed  PubMed Central  Google Scholar 

  • Puliyappadamba VT, Hatanpaa KJ, Chakraborty S, Habib AA (2014) The role of NF-κB in the pathogenesis of glioma. Mol Cell Oncol 1:e963478

    PubMed  PubMed Central  Google Scholar 

  • Renfrow JJ, Soike MH, Debinski W, Ramkissoon SH, Mott RT, Frenkel MB, Sarkaria JN, Lesser GJ, Strowd RE (2018) Hypoxia-inducible factor 2α: a novel target in gliomas. Future Med Chem 10:2227–2236

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roundtree IA, Luo G-Z, Zhang Z, Wang X, Zhou T, Cui Y, Sha J, Huang X, Guerrero L, Xie P (2017) YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs. Elife 6:e31311

    PubMed  PubMed Central  Google Scholar 

  • Schöller E, Weichmann F, Treiber T, Ringle S, Treiber N, Flatley A, Feederle R, Bruckmann A, Meister G (2018) Interactions, localization, and phosphorylation of the m6A generating METTL3–METTL14–WTAP complex. RNA 24:499–512

    PubMed  PubMed Central  Google Scholar 

  • Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, Mertins P, Ter-Ovanesyan D, Habib N, Cacchiarelli D (2014) Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep 8:284–296

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shen D, Wang B, Gao Y, Zhao L, Bi Y, Zhang J, Wang N, Kang H, Pang J, Liu Y (2022) Detailed resume of RNA m6A demethylases. Acta Pharm Sinica B. https://doi.org/10.1016/j.apsb.2022.01.003

    Article  Google Scholar 

  • Shi H, Wei J, He C (2019) Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell 74:640–650

    CAS  PubMed  PubMed Central  Google Scholar 

  • Śledź P, Jinek M (2016) Structural insights into the molecular mechanism of the m6A writer complex. Elife 5:e18434

    PubMed  PubMed Central  Google Scholar 

  • Stevanovic M, Kovacevic-Grujicic N, Mojsin M, Milivojevic M, Drakulic D (2021) SOX transcription factors and glioma stem cells: choosing between stemness and differentiation. World J Stem Cells 13:1417–1445. https://doi.org/10.4252/wjsc.v13.i10.1417

    Article  PubMed  PubMed Central  Google Scholar 

  • Strickland M, Stoll EA (2017) Metabolic reprogramming in glioma. Front Cell Dev Biol 5:43

    PubMed  PubMed Central  Google Scholar 

  • Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, Deng X, Wang Y, Weng X, Hu C (2018) R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 172(90–105):e123

    Google Scholar 

  • Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV (2014) Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157:580–594

    PubMed  PubMed Central  Google Scholar 

  • Suvasini R, Shruti B, Thota B, Shinde SV, Friedmann-Morvinski D, Nawaz Z, Prasanna KV, Thennarasu K, Hegde AS, Arivazhagan A (2011) Insulin growth factor-2 binding protein 3 (IGF2BP3) is a glioblastoma-specific marker that activates phosphatidylinositol 3-kinase/mitogen-activated protein kinase (PI3K/MAPK) pathways by modulating IGF-2. J Biol Chem 286:25882–25890

    CAS  PubMed  PubMed Central  Google Scholar 

  • Talmadge JE, Fidler IJ (2010) AACR centennial series: the biology of cancer metastasis: historical perspective. Can Res 70:5649–5669

    CAS  Google Scholar 

  • TCGA (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061

    Google Scholar 

  • Tran NT, Su H, Khodadadi-Jamayran A, Lin S, Zhang L, Zhou D, Pawlik KM, Townes TM, Chen Y, Mulloy JC (2016) The AS-RBM15 lncRNA enhances RBM15 protein translation during megakaryocyte differentiation. EMBO Rep 17:887–900

    CAS  PubMed  PubMed Central  Google Scholar 

  • Visvanathan A, Patil V, Arora A, Hegde A, Arivazhagan A, Santosh V, Somasundaram K (2018) Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 37:522–533

    CAS  PubMed  Google Scholar 

  • Visvanathan A, Patil V, Abdulla S, Hoheisel JD, Somasundaram K (2019) N6-Methyladenosine landscape of glioma stem-like cells: METTL3 is essential for the expression of actively transcribed genes and sustenance of the oncogenic signaling. Genes 10:141

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J-B, Dong D-F, Wang M-D, Gao K (2014a) IDH1 overexpression induced chemotherapy resistance and IDH1 mutation enhanced chemotherapy sensitivity in glioma cells in vitro and in vivo. Asian Pac J Cancer Prev 15:427–432

    PubMed  Google Scholar 

  • Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G (2014b) N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 505:117–120

    PubMed  Google Scholar 

  • Wang G, Wang J, Zhao H, Wang J, To SST (2015a) The role of Myc and let-7a in glioblastoma, glucose metabolism and response to therapy. Arch Biochem Biophys 580:84–92

    CAS  PubMed  Google Scholar 

  • Wang R-j, Li J-w, Bao B-h, Wu H-c, Du Z-h, Su J-l, Zhang M-h, Liang H-q (2015b) MicroRNA-873 (miRNA-873) inhibits glioblastoma tumorigenesis and metastasis by suppressing the expression of IGF2BP1. J Biol Chem 290:8938–8948

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H, He C (2015c) N6-methyladenosine modulates messenger RNA translation efficiency. Cell 161:1388–1399

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang P, Doxtader KA, Nam Y (2016) Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell 63:306–317

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L-c, Chen S-h, Shen X-l, Li D-c, Liu H-y, Ji Y-l, Li M, Yu K, Yang H, Chen J-J (2020) M6A RNA methylation regulator HNRNPC contributes to tumorigenesis and predicts prognosis in glioblastoma multiforme. Front Oncol 10:2021

    Google Scholar 

  • Wei J, Liu F, Lu Z, Fei Q, Ai Y, He PC, Shi H, Cui X, Su R, Klungland A (2018) Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol Cell 71(973–985):e975

    Google Scholar 

  • Wen J, Lv R, Ma H, Shen H, He C, Wang J, Jiao F, Liu H, Yang P, Tan L (2018) Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal. Mol Cell 69(1028–1038):e1026

    Google Scholar 

  • Witsch E, Sela M, Yarden Y (2010) Roles for growth factors in cancer progression. Physiology (bethesda) 25:85–101. https://doi.org/10.1152/physiol.00045.2009

    Article  CAS  PubMed  Google Scholar 

  • Wu B, Su S, Patil DP, Liu H, Gan J, Jaffrey SR, Ma J (2018) Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1. Nat Commun 9:1–12

    Google Scholar 

  • Wu C, Ma H, Qi G, Chen F, Chu J (2019) Insulin-like growth factor II mRNA-binding protein 3 promotes cell proliferation, migration and invasion in human glioblastoma. Onco Targets Ther 12:3661

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xi Z, Xue Y, Zheng J, Liu X, Ma J, Liu Y (2016) WTAP expression predicts poor prognosis in malignant glioma patients. J Mol Neurosci 60:131–136

    CAS  PubMed  Google Scholar 

  • Xi Z, Wang P, Xue Y, Shang C, Liu X, Ma J, Li Z, Li Z, Bao M, Liu Y (2017) Overexpression of miR-29a reduces the oncogenic properties of glioblastoma stem cells by downregulating quaking gene isoform 6. Oncotarget 8:24949

    PubMed  PubMed Central  Google Scholar 

  • Xia Z, Tang M, Ma J, Zhang H, Gimple RC, Prager BC, Tang H, Sun C, Liu F, Lin P (2021) Epitranscriptomic editing of the RNA N6-methyladenosine modification by dCasRx conjugated methyltransferase and demethylase. Nucleic Acids Res 49:7361–7374

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao W, Adhikari S, Dahal U, Chen Y-S, Hao Y-J, Sun B-F, Sun H-Y, Li A, Ping X-L, Lai W-Y (2016) Nuclear m6A reader YTHDC1 regulates mRNA splicing. Mol Cell 61:507–519

    CAS  PubMed  Google Scholar 

  • Xu C, Wang X, Liu K, Roundtree IA, Tempel W, Li Y, Lu Z, He C, Min J (2014) Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat Chem Biol 10:927–929

    CAS  PubMed  Google Scholar 

  • Yamini B (2018) NF-κB, mesenchymal differentiation and glioblastoma. Cells 7:125

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Hsu PJ, Chen Y-S, Yang Y-G (2018) Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res 28:616–624

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang K, Wu Z, Zhang H, Zhang N, Wu W, Wang Z, Dai Z, Zhang X, Zhang L, Peng Y (2022) Glioma targeted therapy: insight into future of molecular approaches. Mol Cancer 21:1–32

    Google Scholar 

  • Yu J, Chen M, Huang H, Zhu J, Song H, Zhu J, Park J, Ji S-J (2018) Dynamic m6A modification regulates local translation of mRNA in axons. Nucleic Acids Res 46:1412–1423

    CAS  PubMed  Google Scholar 

  • Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, Cheng T, Gao M, Shu X, Ma H (2018) VIRMA mediates preferential m6A mRNA methylation in 3′ UTR and near stop codon and associates with alternative polyadenylation. Cell Discov 4:1–17

    CAS  Google Scholar 

  • Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O (2017) m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell 31(591–606):e596

    Google Scholar 

  • Zhang Z, Wang Z, Huang K, Liu Y, Wei C, Zhou J, Zhang W, Wang Q, Liang H, Zhang A (2019) PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma. Cancer Lett 443:91–107

    CAS  PubMed  Google Scholar 

  • Zhang N, Zuo Y, Peng Y, Zuo L (2021) Function of N6-Methyladenosine Modification in Tumors. J Oncol. https://doi.org/10.1155/2021/6461552

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao R, Hu M, Liang S, Wang B, Yu B, Yang G, Qian D (2019) IE86 Inhibits the apoptosis and promotes the cell proliferation of glioma cells via the hnRNP A2/B1-mediated alternative splicing of Bcl-x. Int J Clin Exp Pathol 12:2775

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao R, Li B, Zhang S, He Z, Pan Z, Guo Q, Qiu W, Qi Y, Zhao S, Wang S (2021) The N6-Methyladenosine-modified pseudogene HSPA7 CORRELATES With the tumor microenvironment and predicts the response to immune checkpoint therapy in glioblastoma. Front Immunol. https://doi.org/10.3389/fimmu.2021.653711

    Article  PubMed  PubMed Central  Google Scholar 

  • Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang C-M, Li CJ, Vågbø CB, Shi Y, Wang W-L, Song S-H (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49:18–29

    CAS  PubMed  Google Scholar 

  • Zhong C, Tao B, Yang F, Xia K, Yang X, Chen L, Peng T, Xia X, Li X, Peng L (2021) Histone demethylase JMJD1C promotes the polarization of M1 macrophages to prevent glioma by upregulating miR-302a. Clin Transl Med 11:e424

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu X, Yang H, Zhang M, Wu X, Jiang L, Liu X, Lv K (2021) YTHDC1-mediated VPS25 regulates cell cycle by targeting JAK-STAT signaling in human glioma cells. Cancer Cell Int 21:1–14

    Google Scholar 

Download references

Funding

The study was supported by Youth Program of National Natural Science Foundation of China (No. 82000559).

Author information

Authors and Affiliations

  1. The Second Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of China

    Zhouhan Xu

  2. Department of Neurosurgery, The Second Hospital of Shandong University, 247 Beiyuan Road, Jinan, 250012, Shandong, People’s Republic of China

    Jun Jiang

  3. Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, 250012, Shandong, People’s Republic of China

    Shun Wang

Authors
  1. Zhouhan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JJ designed the work, XZ wrote the manuscript and prepared the figures and tables, and Wang Shun revised the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Jun Jiang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, Z., Jiang, J. & Wang, S. The Critical Role of RNA m6A Methylation in Gliomas: Targeting the Hallmarks of Cancer. Cell Mol Neurobiol 43, 1697–1718 (2023). https://doi.org/10.1007/s10571-022-01283-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-022-01283-8

Keywords

Search

Navigation