RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail

Xinyao Lin; Guoshi Chai; Yingmin Wu; Jiexin Li; Feng Chen; Jianzhao Liu; Guanzheng Luo; Jordi Tauler; Jun Du; Shuibin Lin; Chuan He; Hongsheng Wang

doi:10.1038/s41467-019-09865-9

RNA m⁶A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail

Nat Commun. 2019 May 6;10(1):2065. doi: 10.1038/s41467-019-09865-9.

Authors

Xinyao Lin¹, Guoshi Chai², Yingmin Wu¹, Jiexin Li¹, Feng Chen¹, Jianzhao Liu^{3

4}, Guanzheng Luo^{2

3}, Jordi Tauler³, Jun Du¹, Shuibin Lin⁵, Chuan He³, Hongsheng Wang⁶

Affiliations

¹ Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
² MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China.
³ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL, 60637, USA.
⁴ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China.
⁵ Department of Rehabilitation Medicine, Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China. whongsh@mail.sysu.edu.cn.

Abstract

N6-Methyladenosine (m⁶A) modification has been implicated in the progression of several cancers. We reveal that during epithelial-mesenchymal transition (EMT), one important step for cancer cell metastasis, m⁶A modification of mRNAs increases in cancer cells. Deletion of methyltransferase-like 3 (METTL3) down-regulates m⁶A, impairs the migration, invasion and EMT of cancer cells both in vitro and in vivo. m⁶A-sequencing and functional studies confirm that Snail, a key transcription factor of EMT, is involved in m⁶A-regulated EMT. m⁶A in Snail CDS, but not 3'UTR, triggers polysome-mediated translation of Snail mRNA in cancer cells. Loss and gain functional studies confirm that YTHDF1 mediates m⁶A-increased translation of Snail mRNA. Moreover, the upregulation of METTL3 and YTHDF1 act as adverse prognosis factors for overall survival (OS) rate of liver cancer patients. Our study highlights the critical roles of m⁶A on regulation of EMT in cancer cells and translation of Snail during this process.

Publication types

Research Support, Non-U.S. Gov't
Retracted Publication

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / metabolism
Animals
Cell Line, Tumor
Down-Regulation
Epithelial-Mesenchymal Transition / genetics*
Female
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Kaplan-Meier Estimate
Liver / pathology
Liver Neoplasms / genetics*
Liver Neoplasms / mortality
Liver Neoplasms / pathology
Methylation
Methyltransferases / genetics
Methyltransferases / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
RNA / metabolism*
RNA Processing, Post-Transcriptional
RNA-Binding Proteins / metabolism
Snail Family Transcription Factors / genetics*
Tissue Array Analysis
Up-Regulation
Xenograft Model Antitumor Assays

Substances

RNA-Binding Proteins
SNAI1 protein, human
Snail Family Transcription Factors
YTHDF1 protein, human
RNA
N-methyladenosine
Methyltransferases
METTL3 protein, human
Adenosine