Methylation of N6-methyladenosine (m6A) messenger RNA is a gene regulation mechanism that affects cell differentiation and proliferation in development and cancer.
Researchers analyzed human endometrial cancer with a hotspot R298P mutation in a major component of the methyltransferase complex to evaluate the functions of m6A mRNA methylation in cell proliferation and tumorigenicity (METTL14). They discovered that over 70% of endometrial tumors had decreased m6A methylation, which is likely related to either this METTL14 mutation or decreased expression of METTL3, another component of the methyltransferase complex. These alterations boost the proliferation and tumorigenicity of endometrial cancer cells, most likely via activating the AKT pathway.
Reduced m6A methylation lowers the expression of the negative AKT regulator PHLPP2 while increasing the expression of the positive AKT regulator mTORC2. These findings point to diminished m6A mRNA methylation as an oncogenic pathway in endometrial cancer, as well as m6A methylation as a regulator of AKT signaling.