National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Jan 25;55(1):103-116. doi: 10.3724/abbs.2023002.
Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system (CNS) tumors. N6-methyladenine (m6A) RNA modification is a main type of RNA modification in eukaryotic cells. In this study, we find that the m6A RNA methylation eraser FTO is dramatically downregulated in glioma samples and cell lines, particularly in intermediate and core regions and hypoxia-challenged glioma cells. , FTO overexpression inhibits the hypoxia-induced capacities of glioma cells to proliferate, migrate and invade, and decreases the percentage of cells with m6A RNA methylation. , FTO overexpression inhibits tumor growth in the xenograft model and decreases the protein levels of migration markers, including Vimentin and Twist. miR-27a-3p is upregulated within glioma intermediate and core regions and hypoxia-challenged glioma cells. miR-27a-3p inhibits the expression of FTO via direct binding to FTO. miR-27a-3p overexpression promotes hypoxia-challenged glioma cell aggressiveness, whereas FTO overexpression partially diminishes the oncogenic effects of miR-27a-3p overexpression. FTO overexpression promotes the nuclear translocation of FOXO3a and upregulates the expression levels of the FOXO3a downstream targets BIM, BNIP3, BCL-6, and PUMA, possibly by interacting with FOXO3a. Conclusively, FTO serves as a tumor suppressor in glioma by suppressing hypoxia-induced malignant behaviors of glioma cells, possibly by promoting the nuclear translocation of FOXO3a and upregulating FOXO3a downstream targets. miR-27a-3p is a major contributor to FTO downregulation in glioma under hypoxia.
多形性胶质母细胞瘤（GBM）是中枢神经系统（CNS）最恶性的肿瘤类型之一。N6-甲基腺嘌呤（m6A）RNA 修饰是真核细胞中主要的 RNA 修饰类型。在本研究中，我们发现 m6A RNA 甲基化清除酶 FTO 在胶质瘤样本和细胞系中显著下调，特别是在中间区和核心区以及缺氧挑战的胶质瘤细胞中。FTO 过表达抑制缺氧诱导的胶质瘤细胞增殖、迁移和侵袭能力，并降低 m6A RNA 甲基化细胞的百分比。FTO 过表达抑制异种移植模型中的肿瘤生长，并降低迁移标志物包括波形蛋白和 Twist 的蛋白水平。miR-27a-3p 在胶质瘤中间区和核心区以及缺氧挑战的胶质瘤细胞中上调。miR-27a-3p 通过直接结合 FTO 抑制 FTO 的表达。miR-27a-3p 过表达促进缺氧挑战的胶质瘤细胞侵袭性，而 FTO 过表达部分减弱 miR-27a-3p 过表达的致癌作用。FTO 过表达促进 FOXO3a 的核转位，并上调 FOXO3a 下游靶标 BIM、BNIP3、BCL-6 和 PUMA 的表达水平，可能通过与 FOXO3a 相互作用。总之，FTO 作为胶质瘤中的肿瘤抑制因子，通过抑制缺氧诱导的胶质瘤细胞恶性行为发挥作用，可能通过促进 FOXO3a 的核转位并上调 FOXO3a 下游靶标。miR-27a-3p 是缺氧条件下胶质瘤中 FTO 下调的主要贡献者。
