m(6)A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer

N(6)-methyladenosine (m(6)A) mRNA 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 ~70% of endometrial tumors exhibit reductions in m(6)A methylation that are likely 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 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 signaling.