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Aberrant mRNA m6A methylation promotes the progression of endometrial cancer by altering Akt activity

ABSTRACT: The N6-methyladenosine (m6A) methylation of mRNA is an emerging gene regulatory mechanism that controls the stability and translation of methylated transcripts in development and cell differentiation. Here, we show that aberrant m6A methylation plays key roles in the progression of endometrial cancer. About 70% of endometrial tumors exhibit reduced m6A methylation due to either mutation in METTL14 (~10%) or decreased expression of METTL3 (~60%). The reduction of mRNA m6A methylation through METTL14 mutation or METTL3 downregulation increased the proliferation and tumorigenicity of endometrial cancer cells in vitro and in vivo. RNA-seq and m6A-seq of human tumor tissue identified several transcripts in the Akt pathway exhibiting altered m6A methylation, including PHLPP2 and components of mTORC2. The altered stability and translation of these transcripts mediated the increased proliferation of cells with reduced mRNA m6A methylation. These results establish aberrant m6A methylation as a critical oncogenic mechanism underlying a majority of endometrial cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93911 | GEO | 2018/01/22

REPOSITORIES: GEO

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