作者
Xueju Wei,Yue Huo,Jingnan Pi,Yufeng Gao,Shuan Rao,Manman He,Qinglv Wei,Peng Song,Yi‐Ying Chen,Dongxu Lu,Wei Song,Junbo Liang,Lingjie Xu,Haixia Wang,Guolin Hong,Yuehong Guo,Yanmin Si,Jiayue Xu,Xiaoshuang Wang,Yanni Ma,Shuyang Yu,Dongling Zou,Jing Jin,Fang Wang,Jia Yu
摘要
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.