机构：[1]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.[2]The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, China.[3]Department of Laboratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen Key Laboratory of Genetic Testing, School of Medicine, Xiamen University, Xiamen, China.[4]Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.[5]Department of Oncology, Second Medical Center of Chinese PLA General Hospital, Beijing, China.[6]Emergency Department of West China Hospital, Sichuan University, Chengdu, China.[7]Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China.[8]State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.[9]Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.[10]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Wei et al. identify that cytoplasmic METTL3 interacts with PABPC1 to facilitate translation of epigenetic factor mRNAs without m(6)A modification to promote tumour progression, suggesting an m(6)A-independent mechanism for this methyltransferase. METTL3 encodes the predominant catalytic enzyme to promote m(6)A 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 m(6)A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m(6)A modification, but also bind to numerous non-m(6)A-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 m(6)A 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.
基金：
This work was funded by National Key Research and Development Program of China
(2019YFA0801800 to J.Y., 2021YFA1102400 to F.W. and 2019YFA0111700 to X.W.);
the National Natural Science Foundation of China (81530007 and 31725013 to J.Y.,
82022001 and 81970103 to F.W., 82100135 to Y.G. and 82073129 to D.Z.); the CAMS
Innovation Fund for Medical Sciences (2021-I2M-1-019 to J.Y. and 2021-I2M-1-040 to
F.W.); the Fundamental Research Funds for the Core Facility (3332019001), the CAMS
(2016GH310001 to J.Y., 2017-I2M-B&R-04 to J.Y. and 2018RC310013 to F.W.) and
the Medical Epigenetics Research Center, CAMS (2017PT31035); Outstanding Youths
Development scheme of Nanfang Hospital, Southern Medical University (2020J001 to
S.R.) and Outstanding Youths Development program, Southern Medical University
(2019YQPY006 to S.R.). The open-access charge was funded by the National Key
Research and Development Program of China (2019YFA0801800 to J.Y.).
第一作者机构：[1]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.[2]The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, China.[3]Department of Laboratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen Key Laboratory of Genetic Testing, School of Medicine, Xiamen University, Xiamen, China.
共同第一作者：
通讯作者：
通讯机构：[1]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.[2]The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, China.[9]Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.[10]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
推荐引用方式(GB/T 7714)：
Wei Xueju,Huo Yue,Pi Jingnan,et al.METTL3 preferentially enhances non-m(6)A translation of epigenetic factors and promotes tumourigenesis[J].NATURE CELL BIOLOGY.2022,24(8):1278-+.doi:10.1038/s41556-022-00968-y.
APA：
Wei, Xueju,Huo, Yue,Pi, Jingnan,Gao, Yufeng,Rao, Shuan...&Yu, Jia.(2022).METTL3 preferentially enhances non-m(6)A translation of epigenetic factors and promotes tumourigenesis.NATURE CELL BIOLOGY,24,(8)
MLA：
Wei, Xueju,et al."METTL3 preferentially enhances non-m(6)A translation of epigenetic factors and promotes tumourigenesis".NATURE CELL BIOLOGY 24..8(2022):1278-+
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