METTL3的O-GlcNAc糖基化通过以m6A-IGF2BP3依赖性方式上调MCM10表达驱动肝细胞癌进展
陈震 等
m6A甲基转移酶METTL3是介导RNA发生m6A修饰的关键调控因子，在癌症发展中起重要作用。尽管METTL3在肝细胞癌（HCC）中意义重大，但其翻译后修饰及其在肝癌中的功能影响仍知之甚少。本研究揭示METTL3可以发生O-连接N-乙酰葡糖胺修饰（O-GlcNAcylation），该修饰可增强METTL3蛋白质稳定性并促进肝癌进展。我们首次鉴定出METTL3蛋白具有三个O-GlcNAc修饰位点（T186/S192/S193）。这些位点的O-GlcNAc修饰减少了METTL3的泛素化，从而使其蛋白更加稳定，并增强其与WTAP蛋白的相互作用，从而维持肝癌细胞中的m6A修饰水平。进一步机制解析发现，METTL3的O-GlcNAc糖基化通过以m6A-IGF2BP3依赖性方式稳定微小染色体维持蛋白10（MCM10）的mRNA，从而上调MCM10的表达。通过设计多肽靶向抑制METTL3的O-GlcNAc糖基化，在体外和体内均能有效抑制肝癌生长。综上，本研究揭示了O-GlcNAc糖基化在调控m6A表观转录组中的关键作用，并为靶向METTL3 O-GlcNAc修饰作为肝癌治疗策略提供了理论依据。
O-GlcNAcylation of METTL3 drives hepatocellular carcinoma progression by upregulating MCM10 expression in an m6A-IGF2BP3-dependent manner
Zhen Chen (陈震), Jiaxin Yin（印家鑫）, Zhongqi Feng（冯中奇）, Yanlai Zhang, Li Liang, Xiaojun Wang, Kai Wang & Ni Tang
Abstract
The m6A methyltransferase METTL3 is a key regulator of RNA m6A modification, which plays a critical role in cancer development. Despite the significance of METTL3 in hepatocellular carcinoma (HCC), its post-translational modifications and their functional implications in HCC remain poorly understood. The present study reveals that METTL3 undergoes O-GlcNAcylation, which enhances its stability and promotes HCC progression. Specific O-GlcNAcylation sites (T186/S192/S193) in METTL3 are identified. O-GlcNAc modification reduces METTL3 ubiquitination, thereby increasing protein stability, and enhances its interaction with WTAP, thereby sustaining m6A levels in hepatoma cells. Notably, METTL3 O-GlcNAcylation upregulates the expression of minichromosome maintenance protein 10 (MCM10) by stabilizing its mRNA via an m6A-IGF2BP3-dependent manner. Targeting METTL3 O-GlcNAcylation with designed peptides effectively inhibits HCC growth both in vitro and in vivo. Collectively, our findings provide insights into the regulatory role of O-GlcNAcylation in modulating the m6A epitranscriptome and suggest the potential therapeutic relevance of targeting METTL3 O-GlcNAcylation in HCC.
DOI：https://doi.org/10.1038/s41419-025-07844-1
原文链接：https://www.nature.com/articles/s41419-025-07844-1
