Chen Zhen, Yin Jiaxin, Feng Zhongqi, Zhang Yanlai, Liang Li, Wang Xiaojun, Wang Kai, Tang Ni
Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Cell Death Dis. 2025 Jul 12;16(1):518. doi: 10.1038/s41419-025-07844-1.
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.
m6A甲基转移酶METTL3是RNA m6A修饰的关键调节因子，在癌症发展中起关键作用。尽管METTL3在肝细胞癌（HCC）中具有重要意义，但其翻译后修饰及其在HCC中的功能意义仍知之甚少。本研究揭示METTL3发生O-GlcNAc糖基化修饰，这增强了其稳定性并促进HCC进展。确定了METTL3中特定的O-GlcNAc糖基化位点（T186/S192/S193）。O-GlcNAc修饰减少了METTL3的泛素化，从而提高了蛋白质稳定性，并增强了其与WTAP的相互作用，从而维持肝癌细胞中的m6A水平。值得注意的是，METTL3的O-GlcNAc糖基化修饰通过m6A-IGF2BP3依赖性方式稳定微小染色体维持蛋白10（MCM10）的mRNA，从而上调其表达。用设计的肽靶向METTL3的O-GlcNAc糖基化修饰可有效抑制体外和体内HCC的生长。总的来说，我们的研究结果为O-GlcNAc糖基化修饰在调节m6A表观转录组中的调控作用提供了见解，并表明靶向METTL3的O-GlcNAc糖基化修饰在HCC中的潜在治疗意义。
