机构：[1]Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA[2]Howard Hughes Medical Institute,Chicago, IL, USA[3]Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, IL, USA[4]Centerfor Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China[5]College of Chemistry, Sichuan University, Chengdu, China[6]Committeeon Cancer Biology and Medical Scientist Training Program, The University of Chicago, Chicago, IL, USA[7]Department of Pathology, Zhongnan Hospitalof Wuhan University, Wuhan, China[8]Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Zhongnan Hospitalof Wuhan University, Wuhan, China[9]Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China[10]MOE KeyLaboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China[11]Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA
N6-methyladenosine (m6A) messenger RNA methylation is a gene regulatory mechanism affecting cell differentiation and proliferation in development and cancer. To study the roles of m6A mRNA methylation in cell proliferation and tumorigenicity, we investigated human endometrial cancer in which a hotspot R298P mutation is present in a key component of the methyltransferase complex (METTL14). We found that about 70% of endometrial tumours exhibit reductions in m6A methylation that are probably due to either this METTL14 mutation or reduced expression of METTL3, another component of the methyltransferase complex. These changes lead to increased proliferation and tumorigenicity of endometrial cancer cells, likely through activation of the AKT pathway. Reductions in m6A methylation lead to decreased expression of the negative AKT regulator PHLPP2 and increased expression of the positive AKT regulator mTORC2. Together, these results reveal reduced m6A mRNA methylation as an oncogenic mechanism in endometrial cancer and identify m6A methylation as a regulator of AKT signalling.
基金：
This work was supported by a Marsha
Rivkin Foundation award (M.A.E.); University of Chicago Institute for Biophysical
Dynamics Yen Fellowship (B.T.H.); National Natural Science Foundation of China
grants 81472023 and 81271919 (S.L.); The National Basic Research Programme grants
2012CB720600 and 2012CB720605 (S.L.); the National Key Research and Development
Programme of China 2017YFA0506800 (Jz.L.); the Thousands Young Talents Plan of
China and Hundreds Talents Programme of Zhejiang University (Jz.L.); National Cancer
Institute grants CA111882 (E.L.) and F32 CA221007 (B.T.H.); National Institutes of
Health grants R01 HG008688 and RM1 HG008935 (C.H.); and University of Chicago
Cancer Center Support Grant P30CA014599. M.A.E. thanks the Harris Family
Foundation for their generous support. C.H. is an investigator of the Howard Hughes
Medical Institute.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2018]版：
大类|1 区生物
小类|1 区细胞生物学
最新[2023]版：
大类|1 区生物学
小类|1 区细胞生物学
第一作者：
第一作者机构：[1]Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA[2]Howard Hughes Medical Institute,Chicago, IL, USA
共同第一作者：
通讯作者：
通讯机构：[1]Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA[2]Howard Hughes Medical Institute,Chicago, IL, USA[11]Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA
推荐引用方式(GB/T 7714)：
Liu Jun,Eckert Mark A,Harada Bryan T,et al.m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer.[J].Nature cell biology.2018,20(9):1074-1083.doi:10.1038/s41556-018-0174-4.
APA：
Liu Jun,Eckert Mark A,Harada Bryan T,Liu Song-Mei,Lu Zhike...&He Chuan.(2018).m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer..Nature cell biology,20,(9)
MLA：
Liu Jun,et al."m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer.".Nature cell biology 20..9(2018):1074-1083
生物