Zhang Junhao, Li Guoxi, Wu Runqiu, Shi Lin, Tian Cong, Jiang Hongyan, Che Hongyu, Jiang Yongang, Jin Zhiyong, Yu Rutong, Liu Xuejiao, Zhang Xu
Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Xinxiang Central Hospital, Xinxiang 453003, Henan, China.
Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Cell Signal. 2025 Aug;132:111782. doi: 10.1016/j.cellsig.2025.111782. Epub 2025 Apr 2.
Glioblastoma (GBM) was the most common and deadliest malignant brain tumor in adults, with a poor prognosis. Effective targeted drugs are still lacking, and the presence of glioblastoma stem cells (GSC) is a major factor contributing to radiotherapy resistance. Screening for targeted drugs that can sensitize GBM to radiotherapy is crucial. FTO is considered an attractive potential target for tumor therapy, as it mediates m6A demethylation to regulate the stability of target genes. In this study, we evaluated the role of FTO inhibition in promoting the sensitivity of GSC cells to radiotherapy through tumor sphere formation assays, cell apoptosis assays, and in situ GSC tumor models. We preliminarily explored the molecular mechanisms by transcriptome sequencing and m6A methylation sequencing to investigate how inhibiting FTO increases radiotherapy sensitivity. The results showed that downregulation of FTO expression or FTO inhibitor FB23-2 combined with radiotherapy significantly inhibited GSC cell proliferation and self-renewal and increased apoptosis. FB23-2 combined with radiotherapy effectively inhibited intracranial tumor growth in mice and prolonged the survival of tumor-bearing mice. Furthermore, FTO inhibition sustained the increase of γH2AX expression induced by radiotherapy while decreasing Rad51 expression. Importantly, we found that inhibiting FTO could increase m6A methylation modification of VEGFA, thereby downregulating both mRNA and protein expression of VEGFA. Our findings provide a new therapeutic strategy for enhancing GBM radiotherapy sensitivity and lay the theoretical and experimental groundwork for clinical trials targeting FTO.
胶质母细胞瘤（GBM）是成人中最常见且最致命的恶性脑肿瘤，预后较差。目前仍缺乏有效的靶向药物，而胶质母细胞瘤干细胞（GSC）的存在是导致放疗抵抗的主要因素。筛选能够使GBM对放疗敏感的靶向药物至关重要。FTO被认为是肿瘤治疗中一个有吸引力的潜在靶点，因为它介导m6A去甲基化以调节靶基因的稳定性。在本研究中，我们通过肿瘤球形成试验、细胞凋亡试验和原位GSC肿瘤模型，评估了FTO抑制在促进GSC细胞对放疗敏感性方面的作用。我们通过转录组测序和m6A甲基化测序初步探索了分子机制，以研究抑制FTO如何提高放疗敏感性。结果表明，FTO表达下调或FTO抑制剂FB23 - 2与放疗联合使用可显著抑制GSC细胞增殖和自我更新，并增加细胞凋亡。FB23 - 2与放疗联合使用有效抑制了小鼠颅内肿瘤生长，并延长了荷瘤小鼠的生存期。此外，FTO抑制持续增加放疗诱导的γH2AX表达，同时降低Rad51表达。重要的是，我们发现抑制FTO可增加VEGFA的m6A甲基化修饰，从而下调VEGFA的mRNA和蛋白表达。我们的研究结果为提高GBM放疗敏感性提供了一种新的治疗策略，并为针对FTO的临床试验奠定了理论和实验基础。
