Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Department of Obstetrics and Gynecology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Cell Signal. 2022 Oct;98:110406. doi: 10.1016/j.cellsig.2022.110406. Epub 2022 Jul 14.
N6-methyladenosine (m6A), the most abundant internal modification on mRNAs in eukaryotes, plays a role in endometriosis (EMs). However, the underlying mechanism remains largely unclear. Here, we found that FTO is downregulated in EMs; and plays an important role in regulating glycolysis, proliferation, and metastasis of ectopic endometriotic stromal cells (EESCs) by targeting ATG5. We demonstrated that FTO promotes ATG5 expression in a m6A-dependent manner, and further studies revealed that PKM2 is a target of ATG5. Upon FTO overexpression, increased ATG5 protein expression at low m6A levels inhibited the expression of PKM2, thereby reducing the glycolysis level of EESCs. In addition, we demonstrated through in vitro functional experiments that FTO regulates glycolysis, proliferation, and metastasis of EESCs through the ATG5/PKM2 axis. In conclusion, these findings reveal the functional importance of the m6A methylation mechanism of FTO in regulating the development of EMs, which expands our understanding of this interaction, which is crucial for the development of therapeutic strategies for EMs.
N6-甲基腺苷（m6A）是真核生物中 mRNA 上最丰富的内部修饰物，在子宫内膜异位症（EMs）中发挥作用。然而，其潜在机制在很大程度上仍不清楚。在这里，我们发现 FTO 在 EMs 中下调；并通过靶向 ATG5 ，在调节异位子宫内膜基质细胞（EESCs）的糖酵解、增殖和转移方面发挥重要作用。我们证明 FTO 以 m6A 依赖性方式促进 ATG5 的表达，进一步的研究表明 PKM2 是 ATG5 的靶标。在 FTO 过表达时，低 m6A 水平下增加的 ATG5 蛋白表达抑制了 PKM2 的表达，从而降低了 EESCs 的糖酵解水平。此外，我们通过体外功能实验证明，FTO 通过 ATG5/PKM2 轴调节 EESCs 的糖酵解、增殖和转移。总之，这些发现揭示了 FTO 的 m6A 甲基化机制在调节 EMs 发生发展中的功能重要性，这扩展了我们对这种相互作用的理解，对于 EMs 的治疗策略的发展至关重要。
