Journal
NATURE CELL BIOLOGY
Volume 20, Issue 9, Pages 1074-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41556-018-0174-4
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Funding
- Marsha Rivkin Foundation
- University of Chicago Institute for Biophysical Dynamics Yen Fellowship
- National Natural Science Foundation of China [81472023, 81271919]
- National Basic Research Programme [2012CB720600, 2012CB720605]
- National Key Research and Development Programme of China [2017YFA0506800]
- Thousands Young Talents Plan of China
- Hundreds Talents Programme of Zhejiang University
- National Cancer Institute [CA111882, F32 CA221007]
- National Institutes of Health [R01 HG008688, RM1 HG008935]
- University of Chicago Cancer Center [P30CA014599]
- Harris Family Foundation
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N-6-methyladenosine (m(6)A) messenger RNA methylation is a gene regulatory mechanism affecting cell differentiation and proliferation in development and cancer. To study the roles of m(6)A 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 m(6)A 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 m(6)A 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 m(6)A mRNA methylation as an oncogenic mechanism in endometrial cancer and identify m(6)A methylation as a regulator of AKT signalling.
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