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The m6A Demethylase ALKBH5 Maintains Stemness and Therapeutic Resistance of Glioblastoma Stem Cells [Polysome-seq]

ABSTRACT: One prevalent modification, N6-methyladenosine (m6A), is a dynamic and reversible process regulated by methyltransferases (the "writers"), demethylases (the "erasers"), and m6A-binding proteins (the "readers"). Its abnormal changes are closely associated with the development and progression of human cancers. m6A demethylases, such as FTO and ALKBH5, eliminate the m6A modification from RNA, thus regulating the overall levels of this modification. Here, we show that the m6A demethylase ALKBH5 is highly expressed after ionizing radiation treatment. We conducted polysome profiling alongside RNA sequencing in both control and ALKBH5-KO GSC 83 cells and identified genes with differential translational efficiency due to ALKBH5 KO. We further elucidated that genes, whose translational efficiencies (TEs) were down-regulated after ALKBH5 knockout, were enriched in stemness properties and DNA repair. Overall, our findings imply that ALKBH5 facilitates the selective translation of mRNAs encoding pathways related to stemness and resistance to therapeutic interventions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285535 | GEO | 2025/01/06

REPOSITORIES: GEO

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Project description:N6-methyladenosine (m6A) occurs extensively on multiple RNA species and is the most abundant internal modification of eukaryotic messenger RNA (mRNA). RNA m6A methylation is a dynamic and reversible process subjected to regulation by three categories of m6A modifier proteins, including m6A methyltransferases/writers (e.g., METTL3/14 methyltransferase complex and METTL16), m6A demethylases/erasers (e.g., FTO and ALKBH5) and m6A binding proteins/readers (e.g., YTH family proteins and IGF2BPs). The dynamic and adjustable nature makes m6A a key regulator in RNA metabolism, and the fate of m6A-modified RNA is modulated by m6A readers. Previous studies have demonstrated that fever can benefit survival of cancer patients, and currently hyperthermia (elevating body temperature beyond normal) is either administered alone or in combination with radiotherapy or chemotherapy to treat various neoplasms with unclear mechanisms. Accruing evidence has revealed favorable effects of fever/hyperthermia in cancer treatment through affecting the properties of oncogenic proteins (e.g., stability, posttranslational modification, ability to interact with other molecules). Accordingly, we sought to investigate whether and how heat stress affects cancer development by m6A modification.

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