m(6)A-Dependent Modulation via IGF2BP3/MCM5/Notch Axis Promotes Partial EMT and LUAD Metastasis

作者全名："Yang, Xia; Bai, Qiaorui; Chen, Weizhong; Liang, Jiaer; Wang, Fang; Gu, Weiqi; Liu, Lei; Li, Quanfeng; Chen, Zishuo; Zhou, Anni; Long, Jianting; Tian, Han; Wu, Jueheng; Ding, Xiaofan; Zhou, Ningning; Li, Mengfeng; Yang, Yi; Cai, Junchao"

作者地址："[Yang, Xia; Bai, Qiaorui; Liang, Jiaer; Wang, Fang; Gu, Weiqi; Tian, Han; Wu, Jueheng; Li, Mengfeng; Cai, Junchao] Sun Yat Sen Univ, Affiliated Hosp 1, Adv Med Technol Ctr, Zhongshan Sch Med, Guangzhou 510080, Peoples R China; [Chen, Weizhong; Zhou, Anni; Yang, Yi] Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Guangzhou 510080, Peoples R China; [Liu, Lei] Chongqing Med Univ, Affiliated Hosp 1, Chongqing Key Lab Mol Oncol & Epigenet, Chongqing 400016, Peoples R China; [Li, Quanfeng] Sun Yat Sen Univ, Affiliated Hosp 8, Dept Orthoped, Guangzhou 518033, Peoples R China; [Chen, Zishuo; Li, Mengfeng] Southern Med Univ, Canc Inst, Shenzhen 510515, Peoples R China; [Long, Jianting] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Oncol, Guangzhou 510080, Peoples R China; [Ding, Xiaofan] Univ Macau, Fac Hlth Sci Bldg, Macau 999078, Peoples R China; [Zhou, Ningning] Sun Yat Sen Univ, Dept Med Oncol, Canc Ctr, Guangzhou 510060, Peoples R China; [Cai, Junchao] Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Peoples R China"

通信作者："Cai, JC (通讯作者)，Sun Yat Sen Univ, Affiliated Hosp 1, Adv Med Technol Ctr, Zhongshan Sch Med, Guangzhou 510080, Peoples R China.; Yang, Y (通讯作者)，Sun Yat Sen Univ, Zhongshan Sch Med, Dept Pharmacol, Guangzhou 510080, Peoples R China.; Cai, JC (通讯作者)，Sun Yat Sen Univ, Key Lab Trop Dis Control, Minist Educ, Guangzhou 510080, Peoples R China."

来源：ADVANCED SCIENCE

ESI学科分类：PHYSICS

WOS号：WOS:000985344600001

JCR分区：Q1

影响因子：14.3

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：lung adenocarcinoma; m(6)A modification; MCM5; Notch signaling; partial EMT

摘要："The importance of mRNA N6-methyladenosine (m(6)A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m(6)A modification is interesting but remains uncharacterized. Here, this work shows that m(6)A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial-mesenchymal-transition (EMT) and confers LUAD cells plasticity to metastasize through m(6)A-dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m(6)A-modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1-mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m(6)A-dependent IGF2BP3-mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m(6)A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD."

基金机构："National Natural Science Foundation of China [82241231, 82030088, 81820108025, 81972730, 81922050, 81572837]; Guangdong Basic and Applied Basic Research Foundation [2023A1515010378, 2020A1515010130]"

基金资助正文："Acknowledgements The authors thank Prof. Hongsheng Wang for providing the dCas13b-ALKBH5 and non-targeting gRNA plasmids. This work was supported by the National Natural Science Foundation of China (No. 82241231, 82030088, 81820108025, 81972730, 81922050, 81572837) and Guangdong Basic and Applied Basic Research Foundation (2023A1515010378, 2020A1515010130)."