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.
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DOI：
10.3390/cancers13010040
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发表时间：
2020-12-25
期刊：
影响因子：
5.2
通讯作者：
Seva C
中科院分区：
文献类型：
--
作者：
Kowalski-Chauvel A;Lacore MG;Arnauduc F;Delmas C;Toulas C;Cohen-Jonathan-Moyal E;Seva C
胶质母细胞瘤干细胞（GBMSC），这是特别耐放射性和侵入性，是负责胶质母细胞瘤（GBM）的高复发率。因此，有一个真实的需要更好地了解这些过程中所涉及的机制，并确定新的因素，可能有针对性的放射增敏GBMSC和降低其侵入能力。在这里，我们报告说，m6 A RNA去甲基化酶ALKBH 5，这是在GBMSCs过表达，促进其放射抗性通过控制同源修复。ALKBH 5也参与了GBMSC的侵袭。这些数据表明，ALKBH 5抑制可能是一种新的方法，放射增敏GBMSCs，并克服其侵袭性。GBM的复发被认为是由于GBMSC，其特别具有化学-放射抗性并且特征在于侵入正常脑的高能力。有证据表明，m6 A RNA甲基化的调节在肿瘤进展中起重要作用。然而，这种mRNA修饰在GBM中的影响研究得很少。我们使用患者来源的GBMSCs来证明RNA去甲基化酶ALKBH 5的高表达通过调节同源重组（HR）来增加辐射抗性。在ALKBH 5下调的细胞中，我们观察到辐射后GBMSC存活率下降，可能是由于DNA损伤修复缺陷。事实上，我们观察到参与HR的几个基因的表达减少，包括CHK 1和RAD 51，以及IR后γ-H2 AX染色的持续性。我们在这项研究中还证明了ALKBH 5通过促进GBMSC的侵袭而有助于GBM的侵袭性。事实上，相对于对照细胞，ALKBH 5缺陷的GBMSC表现出显著降低的侵袭能力。我们的数据表明，ALKBH 5是一个有吸引力的治疗靶点，以克服GBMSCs的辐射抗性和侵袭性。
Glioblastoma 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.
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