Deciphering glioma epitranscriptome: focus on RNA modifications

Piperi, Christina; Markouli, Mariam; Gargalionis, Antonios N.; Papavassiliou, Kostas A.; Papavassiliou, Athanasios G.

doi:10.1038/s41388-023-02746-y

Cited by 7 publications

(12 citation statements)

References 164 publications

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“…Epitranscriptomics is an emerging field in cancer biology and biomedicine, and includes reversible RNA modifications and ADAR-mediated adenosine-to-inosine RNA editing, which in turn affect RNA stability, translation efficiency, secondary structures, subcellular localization, alternative splicing and polyadenylation [ 9 ]. For instance, the m 6 A writer (METTL3), eraser (ALKBH5) and reader (YTHDF2) are overexpressed in GBM, where they regulate GSC self-renewal and tumorigenicity by reducing the mRNA stability of OPTN (thereby downregulating mitophagy) [ 10 ]; as well as stabilizing RNAs of GSC critical genes such as FOXM1 and MYC [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity

Lee,

Chuah,

Yoon

et al. 2024

Cell Death Dis

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Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

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Section: Introductionmentioning

confidence: 99%

METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity

Lee,

Chuah,

Yoon

et al. 2024

Cell Death Dis

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“…Compared to the normal cellular microenvironment, TME is characterized by hypoxia, low pH, high interstitial pressure, high vascular permeability, and an inflammatory response; TME is closely related to GC resistance to TMZ, and long‐term use of TMZ may exacerbate immunosuppression in glioma TME. 81 , 82 Angiogenic factors are particularly active in glioma TME, including transforming growth factor beta, hypoxia‐inducible factor, cyclooxygenase‐2, fibroblast growth factor, and helper T cell 2 cytokines. 83 , 84 Inhibition of the production of angiogenic factors, especially in glioma TME, and blocking the blood supply to the tumor are targets of action of many antiangiogenic agents.…”

Section: Advances In Chemotherapy For Gliomamentioning

confidence: 99%

Nanoparticles for efficient drug delivery and drug resistance in glioma: New perspectives

Liu,

Yang,

et al. 2024

CNS Neurosci Ther

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Gliomas are the most common primary tumors of the central nervous system, with glioblastoma multiforme (GBM) having the highest incidence, and their therapeutic efficacy depends primarily on the extent of surgical resection and the efficacy of postoperative chemotherapy. The role of the intracranial blood–brain barrier and the occurrence of the drug‐resistant gene O6‐methylguanine‐DNA methyltransferase have greatly limited the efficacy of chemotherapeutic agents in patients with GBM and made it difficult to achieve the expected clinical response. In recent years, the rapid development of nanotechnology has brought new hope for the treatment of tumors. Nanoparticles (NPs) have shown great potential in tumor therapy due to their unique properties such as light, heat, electromagnetic effects, and passive targeting. Furthermore, NPs can effectively load chemotherapeutic drugs, significantly reduce the side effects of chemotherapeutic drugs, and improve chemotherapeutic efficacy, showing great potential in the chemotherapy of glioma. In this article, we reviewed the mechanisms of glioma drug resistance, the physicochemical properties of NPs, and recent advances in NPs in glioma chemotherapy resistance. We aimed to provide new perspectives on the clinical treatment of glioma.

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“…A variety of RNA modifications have been reported so far in relation to glioma pathogenesis [ 11 , 12 ]. Apart from the 5'-cap and 3'polyA modifications, N6-methyladenine (m6A) mRNA modification mediates more than 80% of all types of RNA methylation.…”

Section: Introductionmentioning

confidence: 99%

Role of N6-methyladenosine methylation in glioma: recent insights and future directions

Li,

Wang

et al. 2023

Cell Mol Biol Lett

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Glioma is the most pervasive intracranial tumor in the central nervous system (CNS), with glioblastoma (GBM) being the most malignant type having a highly heterogeneous cancer cell population. There is a significantly high mortality rate in GBM patients. Molecular biomarkers related to GBM malignancy may have prognostic values in predicting survival outcomes and therapeutic responses, especially in patients with high-grade gliomas. In particular, N6-methyladenine (m6A) mRNA modification is the most abundant form of post-transcriptional RNA modification in mammals and is involved in regulating mRNA translation and degradation. Cumulative findings indicate that m6A methylation plays a crucial part in neurogenesis and glioma pathogenesis. In this review, we summarize recent advances regarding the functional significance of m6A modification and its regulatory factors in glioma occurrence and progression. Significant advancement of m6A methylation-associated regulators as potential therapeutic targets is also discussed.

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Deciphering glioma epitranscriptome: focus on RNA modifications

Cited by 7 publications

References 164 publications

METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity

METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity

Nanoparticles for efficient drug delivery and drug resistance in glioma: New perspectives

Role of N6-methyladenosine methylation in glioma: recent insights and future directions

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