Abstract
Simple SummaryGlioblastoma stem cells (GBMSCs), which are particularly radio-resistant and invasive, are responsible for the high recurrence of glioblastoma (GBM). Therefore, there is a real need for a better understanding of the mechanisms involved in these processes and to identify new factors that might be targeted to radiosensitize GBMSC and decrease their invasive capability. Here, we report that the m6A RNA demethylase ALKBH5, which is overexpressed in GBMSCs, promotes their radioresistance by controlling the homologous repair. ALKBH5 was also involved in GBMSC invasion. These data suggest that ALKBH5 inhibition might be a novel approach to radiosensitize GBMSCs and to overcome their invasiveness.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.
Highlights
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults
It is speculated that this high recurrence is due to the presence of glioblastoma stem cells (GBMSCs), which are characterized by their ability of self-renewal, the overexpression of stem cell markers, their pluripotent aptitude to differentiate into neural lineages, and their high tumorigenic potential in vivo [2,3]
To determine the role of ALKBH5 in radioresistance, we used GBMSCs derived from three human GBM biopsy specimens (GC1, GC2, GC4) cultured as primary neurospheres, and previously characterized [27,28,29,30]
Summary
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. These tumors exhibit diffuse infiltration into brain tissue, rendering surgical resection difficult and incomplete. GBM are resistant to adjuvant treatments after surgery. Despite the combination of radiotherapy and chemotherapy, most GBM recurs and median survival remains around 15 months [1]. It is speculated that this high recurrence is due to the presence of glioblastoma stem cells (GBMSCs), which are characterized by their ability of self-renewal, the overexpression of stem cell markers, their pluripotent aptitude to differentiate into neural lineages, and their high tumorigenic potential in vivo [2,3]. GBMSCs are chemo-radioresistant and are characterized by a high capacity licenses/by/4.0/)
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