Gou Junjie, Bi Jingjing, Wang Kexin, Lei Lei, Feng Yanli, Tan Zengqi, Gao Jiaojiao, Song Yanan, Kang Enci, Guan Feng, Li Xiang
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an, P. R. China.
Department of Hematology, Provincial People's Hospital, Xi'an, P. R. China.
Cell Commun Signal. 2025 Jan 23;23(1):43. doi: 10.1186/s12964-025-02058-6.
Fat mass and obesity-associated protein (FTO) was the first m6A demethylase identified, which is responsible for eliminating m6A modifications in target RNAs. While it is well-established that numerous cytosolic and nuclear proteins undergo O-GlcNAcylation, the possibility of FTO being O-GlcNAcylated and its functional implications remain unclear. This study found that a negative correlation between FTO expression and O-GlcNAcylation in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The decreased O-GlcNAcylation on FTO can result in diminished m6A modification of SRY-related high mobility group box 4 (SOX4). This led to the promotion of cell apoptosis and inhibition of cell proliferation in MDS/AML. The O-GlcNAcylation of FTO stabilized SOX4 transcripts in an m6A-dependent manner, resulting in increased AKT and MAPK phosphorylation and decreased cell apoptosis. Inhibiting FTO O-GlcNAcylation significantly slowed AML progression in vitro, a finding supported by clinical data in MDS/AML patients. In conclusion, our study highlights the crucial role of FTO O-GlcNAcylation in RNA m6A methylation and the progression of MDS/AML, thereby providing a potential therapeutic avenue for these formidable diseases.
脂肪量与肥胖相关蛋白（FTO）是首个被鉴定出的m6A去甲基化酶，它负责去除靶RNA上的m6A修饰。虽然众多胞质和核蛋白会发生O-连接的N-乙酰葡糖胺糖基化（O-GlcNAcylation）已得到充分证实，但FTO发生O-GlcNAcylation的可能性及其功能影响仍不清楚。本研究发现，骨髓增生异常综合征（MDS）和急性髓系白血病（AML）患者中FTO表达与O-GlcNAcylation呈负相关。FTO上O-GlcNAcylation的减少会导致SRY相关高迁移率族盒4（SOX4）的m6A修饰减弱。这导致MDS/AML中细胞凋亡增加和细胞增殖受到抑制。FTO的O-GlcNAcylation以m6A依赖的方式稳定SOX4转录本，导致AKT和MAPK磷酸化增加以及细胞凋亡减少。抑制FTO的O-GlcNAcylation在体外显著减缓了AML的进展，这一发现得到了MDS/AML患者临床数据的支持。总之，我们的研究突出了FTO的O-GlcNAcylation在RNA m6A甲基化以及MDS/AML进展中的关键作用，从而为这些难治性疾病提供了一条潜在的治疗途径。
