Min Luyao, Huo Fuchun, Zhu Zhiman, Din Lina, Zhang Lin, Xu Yuting, Xing Xuewei, Zhang Peng, Wang Qingling
Department of Pathology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
Department of Pathology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
Cell Signal. 2025 Apr;128:111649. doi: 10.1016/j.cellsig.2025.111649. Epub 2025 Feb 7.
Cervical Cancer (CC) is one of the leading causes of tumor-related deaths among women worldwide, and the mechanisms underlying the anti-ferroptosis of CC cells are still unclear. Methyltransferase like 3 (METTL3) is widely expressed various types of tissues and plays a crucial role in tumorigenesis in part by mediating cell death. However, its regulatory function in CC progression and especially the underlying mechanisms have not been fully elucidated. This study aims to explore the role of METTL3 in the ferroptosis of CC cells. Mechanistically, by MeRIP-seq, we identified COTE-1 as a target of METTL3 mediated m6A modification, and revealed that METTL3-mediated COTE-1 expression was dependent on the m6A reader-dependent manner. Functionally, in vitro and in vivo experiments that METTL3 promotes proliferation and metastasis of CC cells by regulating COTE-1 expression. In addition, the study verified the effect of the METTL3/COTE-1 axis on autophagy-dependent ferroptosis. In summary, METTL3 influences CC progression by mediating COTE-1 to influence autophagy-dependent ferroptosis, representing a potential therapeutic approach for treating CC.
宫颈癌（CC）是全球女性肿瘤相关死亡的主要原因之一，CC细胞抗铁死亡的机制仍不清楚。甲基转移酶样3（METTL3）在多种类型组织中广泛表达，部分通过介导细胞死亡在肿瘤发生中起关键作用。然而，其在CC进展中的调控功能，尤其是潜在机制尚未完全阐明。本研究旨在探讨METTL3在CC细胞铁死亡中的作用。机制上，通过MeRIP-seq，我们鉴定出COTE-1是METTL3介导的m6A修饰的靶标，并揭示METTL3介导的COTE-1表达依赖于m6A阅读蛋白依赖的方式。功能上，体外和体内实验表明METTL3通过调节COTE-1表达促进CC细胞的增殖和转移。此外，该研究验证了METTL3/COTE-1轴对自噬依赖性铁死亡的影响。总之，METTL3通过介导COTE-1影响自噬依赖性铁死亡来影响CC进展，这代表了一种治疗CC的潜在治疗方法。
