State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, China.
Nat Cell Biol. 2022 Aug;24(8):1278-1290. doi: 10.1038/s41556-022-00968-y. Epub 2022 Aug 4.
METTL3 encodes the predominant catalytic enzyme to promote mA 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 mA-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via mA modification, but also bind to numerous non-mA-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 mA 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，促进核内 mA 甲基化。最近，越来越多的证据表明 METTL3 在细胞质中的表达，但它的功能尚未完全理解。在这里，我们证明了 METTL3 通过 mA 非依赖性机制促进肿瘤进展。在胃癌中，METTL3 不仅可以通过 mA 修饰促进癌症进展，还可以与许多非 mA 修饰的 mRNA 结合，提示 METTL3 具有意想不到的作用。从机制上讲，细胞质锚定的 METTL3 与 PABPC1 相互作用，稳定其与帽结合复合物 eIF4F 的结合，这优先促进了没有 mA 修饰的表观遗传因子的翻译。临床研究表明，细胞质中分布的 METTL3 与胃癌的进展高度相关，这一发现可以扩展到前列腺癌。因此，细胞质中的 METTL3 增强了表观遗传 mRNA 的翻译，从而成为癌症进展中的致癌驱动因子，METTL3 的亚细胞分布可以辅助癌症患者的诊断和预后预测。
