The m⁶A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells

Highlights

• METTL3 promotes the translation of important oncogenes such as EGFR and TAZ

• METTL3 promotes translation independent of its catalytic activity and m⁶A readers

• METTL3 interacts with translation initiation machinery to enhance translation

• METTL3 is required for the growth, survival, and invasion of cancer cells

Summary

METTL3 is an RNA methyltransferase implicated in mRNA biogenesis, decay, and translation control through N⁶-methyladenosine (m⁶A) modification. Here we find that METTL3 promotes translation of certain mRNAs including epidermal growth factor receptor (EGFR) and the Hippo pathway effector TAZ in human cancer cells. In contrast to current models that invoke m⁶A reader proteins downstream of nuclear METTL3, we find METTL3 associates with ribosomes and promotes translation in the cytoplasm. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. METTL3 expression is elevated in lung adenocarcinoma and using both loss- and gain-of-function studies, we find that METTL3 promotes growth, survival, and invasion of human lung cancer cells. Our results uncover an important role of METTL3 in promoting translation of oncogenes in human lung cancer.