Insights into the Regulatory Role of m6A Epitranscriptome in Glioblastoma

Galardi, Silvia; Michienzi, Alessandro; Ciafrè, Silvia Anna

doi:10.3390/ijms21082816

Cited by 36 publications

(29 citation statements)

References 65 publications

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“…However, RNA m6A methylation in cancers is little studied. In GBM, m6A RNA demethylases have been clearly identified as oncogenic factors [ 11 ]. Cui et al showed that inhibition of the m6A RNA demethylase FTO with a specific inhibitor decreased GBMSC tumorigenicity [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

Kowalski‐Chauvel

Lacore

Arnauduc

et al. 2020

Cancers

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Recurrence of GBM is thought to be due to GBMSCs, which are particularly chemo-radioresistant and characterized by a high capacity to invade normal brain. Evidence is emerging that modulation of m6A RNA methylation plays an important role in tumor progression. However, the impact of this mRNA modification in GBM is poorly studied. We used patient-derived GBMSCs to demonstrate that high expression of the RNA demethylase, ALKBH5, increases radioresistance by regulating homologous recombination (HR). In cells downregulated for ALKBH5, we observed a decrease in GBMSC survival after irradiation likely due to a defect in DNA-damage repair. Indeed, we observed a decrease in the expression of several genes involved in the HR, including CHK1 and RAD51, as well as a persistence of γ-H2AX staining after IR. We also demonstrated in this study that ALKBH5 contributes to the aggressiveness of GBM by favoring the invasion of GBMSCs. Indeed, GBMSCs deficient for ALKBH5 exhibited a significant reduced invasion capability relative to control cells. Our data suggest that ALKBH5 is an attractive therapeutic target to overcome radioresistance and invasiveness of GBMSCs.

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Section: Introductionmentioning

confidence: 99%

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

Kowalski‐Chauvel

Lacore

Arnauduc

et al. 2020

Cancers

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“…However, based on the evidence that m6A RNA methylation plays a significant role during development (Heck and Wilusz 2019;Li et al 2019;Vu et al 2019), our results suggest that environmental chemicals can influence developmental processes by altering an important layer of post-transcriptional regulation of mRNAs and noncoding RNAs. Furthermore, m6A RNA methylation has been shown to play a key role in normal physiology and metabolism, stress response and in various types of cancer (Engel et al, 2018;Galardi et al 2020;He et al 2019), suggesting additional toxicity mechanisms for environmental chemicals.…”

Section: Discussionmentioning

confidence: 99%

PCB126 exposure revealed alterations in m6A RNA modifications in transcripts associated with AHR activation

Aluru

Karchner

2020

Preprint

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AbstractChemical modifications of proteins, DNA and RNA moieties play critical roles in regulating gene expression. Emerging evidence suggests these RNA modifications (epitranscriptomics) have substantive roles in basic biological processes. One of the most common modifications in mRNA and noncoding RNAs is N6-methyladenosine (m6A). In a subset of mRNAs, m6A sites are preferentially enriched near stop codons, in 3’ UTRs, and within exons, suggesting an important role in the regulation of mRNA processing and function including alternative splicing and gene expression. Very little is known about the effect of environmental chemical exposure on m6A modifications. As many of the commonly occurring environmental contaminants alter gene expression profiles and have detrimental effects on physiological processes, it is important to understand the effects of exposure on this important layer of gene regulation. Hence, the objective of this study was to characterize the acute effects of developmental exposure to PCB126, an environmentally relevant dioxin-like PCB, on m6A methylation patterns. We exposed zebrafish embryos to PCB126 for 6 hours starting from 72 hours post-fertilization and profiled m6A RNA using methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq). Our analysis revealed 117 and 217 m6A peaks in the DMSO and PCB126 samples (FDR 5%), respectively. The majority of the peaks were preferentially located around the 3’UTR and stop codons. Statistical analysis revealed 15 m6A marked transcripts to be differentially methylated by PCB126 exposure. These include transcripts that are known to be activated by AHR agonists (e.g., ahrra, tiparp, nfe2l2b) as well as others that are important for normal development (vgf, cebpd, foxi1). These results suggest that environmental chemicals such as dioxin-like PCBs could affect developmental gene expression patterns by altering m6A levels. Further studies are necessary to understand the functional consequences of exposure-associated alterations in m6A levels.

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“…They studied the levels of m 6 A RNA methylation in three GSC lines and showed that they were reduced uponin vitro differentiation. Moreover, they also found that METTL3 mRNA was clearly more abundant in GSCs compared to counterparts [ 82 , 83 ].…”

Section: Characteristics Of M6a Modification In Gliomasmentioning

confidence: 99%

m6A modification in RNA: biogenesis, functions and roles in gliomas

Zhang

Geng

et al. 2020

J Exp Clin Cancer Res

120

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The chemical modification of RNA is a newly discovered epigenetic regulation mechanism in cells and plays a crucial role in a variety of biological processes. N6-methyladenine (m6A) mRNA modification is the most abundant form of posttranscriptional RNA modification in eukaryotes. Through the development of m6A RNA sequencing, the relevant molecular mechanism of m6A modification has gradually been revealed. It has been found that the effect of m6A modification on RNA metabolism involves processing, nuclear export, translation and even decay. As the most common malignant tumour of the central nervous system, gliomas (especially glioblastoma) have a very poor prognosis, and treatment efficacy is not ideal even with the application of high-intensity treatment measures of surgery combined with chemoradiotherapy. Exploring the origin and development mechanisms of tumour cells from the perspective of tumour biogenesis has always been a hotspot in the field of glioma research. Emerging evidence suggests that m6A modification can play a key role in gliomas through a variety of mechanisms, providing more possibilities for early diagnosis and targeted therapy of gliomas. The aim of the present review is to focus on the research progress regarding the association between m6A modification and gliomas. And to provide a theoretical basis according to the currently available literature for further exploring this association. This review may provide new insights for the molecular mechanism, early diagnosis, histologic grading, targeted therapy and prognostic evaluation of gliomas.

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Insights into the Regulatory Role of m6A Epitranscriptome in Glioblastoma

Cited by 36 publications

References 65 publications

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

PCB126 exposure revealed alterations in m6A RNA modifications in transcripts associated with AHR activation

m6A modification in RNA: biogenesis, functions and roles in gliomas

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