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. |