METTL3 encodes the predominant catalytic enzyme to promote m⁶A methylation in nucleus. Recently, accumulating evidence has shown the expression of METTL3 in cytoplasm, but its function is not fully understood. Here we demonstrated an m⁶A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m⁶A modification, but also bind to numerous non-m⁶A-modified mRNAs, suggesting an unexpected role of METTL3. Mechanistically, cytoplasm-anchored METTL3 interacted with PABPC1 to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m⁶A modification. Clinical investigation showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded to prostate cancer. Therefore, the cytoplasmic METTL3 enhances the translation of epigenetic mRNAs, thus serving as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnosis and predict prognosis for patients with cancer.

METTL3 编码主要的催化酶以促进细胞核中的 m ⁶ A 甲基化。近来，越来越多的证据表明 METTL3 在细胞质中表达，但其功能尚不完全清楚。在这里，我们展示了METTL3 促进肿瘤进展的不依赖m ^{6 A 的机制。}在胃癌中，METTL3 不仅可以通过 m ⁶ A 修饰促进癌症进展，还可以与许多非 m ⁶ A 修饰的 mRNA 结合，这表明 METTL3 具有意想不到的作用。机制上，细胞质锚定的 METTL3 与 PABPC1 相互作用以稳定其与帽结合复合物 eIF4F 的结合，这优先促进没有 m ^{6的表观遗传因子的翻译}一个修改。临床研究表明，细胞质分布的 METTL3 与胃癌进展高度相关，这一发现可以扩展到前列腺癌。因此，细胞质 METTL3 增强了表观遗传 mRNAs 的翻译，从而作为癌症进展的致癌驱动因素，而 METTL3 亚细胞分布有助于癌症患者的诊断和预测预后。