Hu Fangqi, Zhang Song, Chai Jie
Shandong Provincial Key Laboratory of Precision Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University Affiliated Tumor Hospital, Jinan, People's Republic of China.
Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China.
Mol Cancer Res. 2025 Aug 4;23(8):724-738. doi: 10.1158/1541-7786.MCR-24-1168.
As a vital form of posttranscriptional modification, RNA N6-methyladenosine (m6A) methylation dysregulation is usually associated with the pathogenesis of a range of diseases, including cancer, but the function and underlying mechanisms of m6A in regulating gastric cancer initiation and progression are still poorly understood. In this study, we have found that methyltransferase-like 3 (METTL3) and the level of RNA m6A modification were significantly upregulated in gastric cancerous tissues relative to their normal counterparts. In addition, higher METTL3 expression always predicted poorer outcomes for patients with gastric cancer. Methylated RNA sequencing revealed that METTL3 deposited m6A modification on farnesyltransferase, subunit alpha (FNTA) mRNA and accelerated its translation relying on YTH N6-methyladenosine RNA-binding protein 1 recognition. When METTL3 or FNTA expression was silenced in gastric cancer cells, the FNTA-mediated KRAS plasma membrane distribution was disrupted, resulting in downstream MEK/ERK signaling inactivation, which finally contributed to gastric cancer suppression in vitro and in vivo. In summary, our studies revealed a cross-talk between METTL3-mediated RNA methylation and FNTA-mediated protein modification, which synergized to drive gastric cancer progression through orchestrating KRAS/ERK signaling activity.
Targeting the METTL3/FNTA pathway will provide an alternative to overcome the resistance of gastric cancer to canonical KRAS inhibitors.
作为一种重要的转录后修饰形式，RNA N6-甲基腺苷（m6A）甲基化失调通常与包括癌症在内的一系列疾病的发病机制相关，但m6A在调节胃癌发生和进展中的功能及潜在机制仍知之甚少。在本研究中，我们发现相对于正常组织，胃癌组织中甲基转移酶样3（METTL3）和RNA m6A修饰水平显著上调。此外，较高的METTL3表达总是预示着胃癌患者预后较差。甲基化RNA测序显示，METTL3在法尼基转移酶α亚基（FNTA）mRNA上沉积m6A修饰，并依赖YTH N6-甲基腺苷RNA结合蛋白1识别加速其翻译。当胃癌细胞中METTL3或FNTA表达沉默时，FNTA介导的KRAS质膜分布被破坏，导致下游MEK/ERK信号失活，最终在体外和体内抑制胃癌。总之，我们的研究揭示了METTL3介导的RNA甲基化与FNTA介导的蛋白质修饰之间的相互作用，它们协同作用，通过协调KRAS/ERK信号活性来驱动胃癌进展。
靶向METTL3/FNTA途径将为克服胃癌对经典KRAS抑制剂的耐药性提供一种替代方法。
