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

Kowalski‐Chauvel, Aline; Lacore, Marie Géraldine; Arnauduc, Florent; Delmas, Caroline; Toulas, Christine; Cohen-Jonathan-Moyal, Elizabeth; Seva, Catherine

doi:10.3390/cancers13010040

Cited by 61 publications

(44 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, ALKBH5 was found to suppress progression in pancreatic cancer and hepatocellular carcinoma [30,31]. Moreover, ALKBH5 was also suggested to increase glioma stem cell radioresistance by regulating homologous recombination [32]. Meanwhile, Li et al identified ALKBH5 to enhance treatment response to anti-PD-1 therapy in melanoma, colorectal, and potentially other cancers [33].…”

Section: Discussionmentioning

confidence: 99%

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Nie

Zhang

Liu

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. Methods Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. Results ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. Conclusions The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

show abstract

Section: Discussionmentioning

confidence: 99%

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Nie

Zhang

Liu

et al. 2021

J Exp Clin Cancer Res

View full text Add to dashboard Cite

show abstract

“…Nine mammalian homologues have been identified, ALKBH1-8 and the fat mass and obesity associated protein (FTO), with each displaying unique roles in genomic stability ( Fedeles et al, 2015 ). ALKBH5 and FTO are the most well characterized of the AlkB homologs and their silencing or deletion reduces the expression of a number of HR and other repair genes in glioblastoma stem cells ( Kowalski-Chauvel et al, 2020 ) and osteoblasts ( Zhang et al, 2019 ), increasing their susceptibility to genotoxic damage. Interestingly, ALKBH2 and ALKBH3 have been shown biochemically to act as DNA repair enzymes that oxidize 5mC to generate 5hmC, 5fC, and 5caC, similarly to TET enzymes ( Bian et al, 2019 ).…”

Section: Potential Roles For Vitamin C In Genomic Stability Via Modulation Of Additional α-Kgddsmentioning

confidence: 99%

Epigenetic Regulation of Genomic Stability by Vitamin C

et al. 2021

View full text Add to dashboard Cite

DNA methylation plays an important role in the maintenance of genomic stability. Ten-eleven translocation proteins (TETs) are a family of iron (Fe2+) and α-KG -dependent dioxygenases that regulate DNA methylation levels by oxidizing 5-methylcystosine (5mC) to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). These oxidized methylcytosines promote passive demethylation upon DNA replication, or active DNA demethylation, by triggering base excision repair and replacement of 5fC and 5caC with an unmethylated cytosine. Several studies over the last decade have shown that loss of TET function leads to DNA hypermethylation and increased genomic instability. Vitamin C, a cofactor of TET enzymes, increases 5hmC formation and promotes DNA demethylation, suggesting that this essential vitamin, in addition to its antioxidant properties, can also directly influence genomic stability. This review will highlight the functional role of DNA methylation, TET activity and vitamin C, in the crosstalk between DNA methylation and DNA repair.

show abstract

“…et al, 2020 ). The m 6 A-demethylase ALKBH5 has been shown to be overexpressed in patient-derived glioblastoma stem cells and may influence radio-resistance via regulation of DNA damage response genes including Chk1 ( Kowalski-Chauvel et al, 2020 ).…”

Section: A In Brain Disordersmentioning

confidence: 99%

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

Mathoux¹,

Henshall²,

Brennan³

2021

Front. Cell. Neurosci.

View full text Add to dashboard Cite

RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N6-methyladenosine (m6A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m6A, how this influences neuronal development and function and how aberrant m6A signaling may contribute to neurological disease. M6A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m6A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m6A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m6A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m6A, although there in vivo activity and the dynamic nature of this modification requires further study. M6A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m6A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m6A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.

show abstract

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

Cited by 61 publications

References 67 publications

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

Epigenetic Regulation of Genomic Stability by Vitamin C

Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease

Contact Info

Product

Resources

About