m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer

Jun Liu; Mark A Eckert; Bryan T Harada; Song-Mei Liu; Zhike Lu; Kangkang Yu; Samantha M Tienda; Agnieszka Chryplewicz; Allen C Zhu; Ying Yang; Jing-Tao Huang; Shao-Min Chen; Zhi-Gao Xu; Xiao-Hua Leng; Xue-Chen Yu; Jie Cao; Zezhou Zhang; Jianzhao Liu; Ernst Lengyel; Chuan He

doi:10.1038/s41556-018-0174-4

m⁶A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer

Nat Cell Biol. 2018 Sep;20(9):1074-1083. doi: 10.1038/s41556-018-0174-4. Epub 2018 Aug 27.

Authors

Jun Liu^#^{1

2}, Mark A Eckert^#³, Bryan T Harada^#^{1

2}, Song-Mei Liu^#⁴, Zhike Lu^{1

2}, Kangkang Yu^{1

2

5}, Samantha M Tienda³, Agnieszka Chryplewicz³, Allen C Zhu^{1

2

6}, Ying Yang⁴, Jing-Tao Huang⁴, Shao-Min Chen⁴, Zhi-Gao Xu⁷, Xiao-Hua Leng⁸, Xue-Chen Yu⁹, Jie Cao¹⁰, Zezhou Zhang¹⁰, Jianzhao Liu¹⁰, Ernst Lengyel¹¹, Chuan He^{12

13

14}

Affiliations

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 Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁵ College of Chemistry, Sichuan University, Chengdu, China.
⁶ Committee on Cancer Biology and Medical Scientist Training Program, The University of Chicago, Chicago, IL, USA.
⁷ Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁸ Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁹ Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.
¹⁰ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China.
¹¹ Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, IL, USA. elengyel@uchicago.edu.
¹² Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.
¹³ Howard Hughes Medical Institute, Chicago, IL, USA. chuanhe@uchicago.edu.
¹⁴ Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA. chuanhe@uchicago.edu.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / genetics
Adenosine / metabolism
Animals
Carcinogenesis*
Cell Line, Tumor
Cell Proliferation*
Endometrial Neoplasms / enzymology*
Endometrial Neoplasms / genetics
Endometrial Neoplasms / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Mechanistic Target of Rapamycin Complex 2 / genetics
Mechanistic Target of Rapamycin Complex 2 / metabolism
Methylation
Methyltransferases / genetics
Methyltransferases / metabolism
Mice, Nude
Mutation
Phosphoprotein Phosphatases / genetics
Phosphoprotein Phosphatases / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
RNA Processing, Post-Transcriptional*
RNA, Messenger / genetics
RNA, Messenger / metabolism*
RNA, Neoplasm / genetics
RNA, Neoplasm / metabolism*
Signal Transduction
Time Factors
Tumor Burden

Substances

RNA, Messenger
RNA, Neoplasm
N-methyladenosine
METTL14 protein, human
Methyltransferases
METTL3 protein, human
Mechanistic Target of Rapamycin Complex 2
Proto-Oncogene Proteins c-akt
PHLPP2 protein, human
Phosphoprotein Phosphatases
Adenosine

Abstract

Publication types

MeSH terms

Substances

Grants and funding