Shi Jia, Zhang Peng, Dong Xuchen, Yuan Jiaqi, Li Yongdong, Li Suwen, Cheng Shan, Ping Yifang, Dai Xingliang, Dong Jun
Department of Neurosurgery, Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Neurosurgery, Third Affiliated Hospital of Soochow University, Changzhou, China.
Cell Death Discov. 2023 Jan 23;9(1):22. doi: 10.1038/s41420-023-01327-y.
Chemo-resistance hinders the therapeutic efficacy of temozolomide (TMZ) in treating glioblastoma multiforme (GBM). Recurrence of GBM even after combination of maximal tumor resection, concurrent radio-chemotherapy, and systemic TMZ applocation is inevitable and attributed to the high therapeutic resistance of glioma stem cells (GSCs), which can survive, evolve, and initiate tumor tissue remodeling, the underlying mechanisms of GSCs chemo-resistance, have not been fully elucidated up-to-now. Emerging evidence showed that METTL3-mediated N6-methyladenosine (m6A) modification contributed to the self-renew and radio-resistance in GSCs, however, its role on maintenance of TMZ resistance of GSCs has not been clarified and need further investigations. We found that the cell viability and half-maximal inhibitory concentration (IC50) of GSCs against TMZ significantly decreased after GSCs underwent serum-induced differentiation to adherent growth of tumor cells. Besides, METTL3 expression and total m6A modification declined dramatically in consistence with GSCs differentiation. Knockdown of METTL3 weakened self-renew, proliferation and TMZ IC50 of GSCs, whereas enhanced TMZ induced γH2AX level, indicating upregulation of double-strand DNA damage. We also found that mRNA stability of two critical DNA repair genes (MGMT and APNG) was regulated by METTL3-mediated m6A modification. In conclusion, we speculated that METTL3-mediated m6A modification of MGMT and APNG mRNAs played crucial roles on suppression of TMZ sensitivity of GSCs, which suggest a potential new therapeutic target of METTL3 against GBM.
化疗耐药阻碍了替莫唑胺（TMZ）治疗多形性胶质母细胞瘤（GBM）的疗效。即使在最大程度的肿瘤切除、同步放化疗和全身应用TMZ联合治疗后，GBM复发仍不可避免，这归因于胶质瘤干细胞（GSCs）的高治疗耐药性，GSCs能够存活、进化并启动肿瘤组织重塑，GSCs化疗耐药的潜在机制至今尚未完全阐明。新出现的证据表明，METTL3介导的N6-甲基腺苷（m6A）修饰有助于GSCs的自我更新和放疗抵抗，然而，其在维持GSCs对TMZ耐药性中的作用尚未明确，需要进一步研究。我们发现，GSCs在血清诱导分化为贴壁生长的肿瘤细胞后，其对TMZ的细胞活力和半数最大抑制浓度（IC50）显著降低。此外，METTL3表达和总m6A修饰与GSCs分化一致显著下降。敲低METTL3会削弱GSCs的自我更新、增殖和TMZ IC50，而增强TMZ诱导的γH2AX水平，表明双链DNA损伤上调。我们还发现，两个关键DNA修复基因（MGMT和APNG）的mRNA稳定性受METTL3介导的m6A修饰调控。总之，我们推测METTL3介导的MGMT和APNG mRNA的m6A修饰在抑制GSCs对TMZ的敏感性中起关键作用，这提示METTL3可能是针对GBM的一个新的治疗靶点。
