The RNA Methyltransferase METTL3 Promotes Oncogene Translation

The METTL3 RNA methyltransferase is a “writer” protein responsible for the N⁶-methyladenosine (m⁶A) modification, and is involved in mRNA biogenesis, decay, and translation. Although m⁶A has been implicated in diverse biological processes, its mechanisms of action remain unclear. In emerging models, m⁶A methyl reader proteins bind to m⁶A and mediate effects downstream of METTL3. However, Lin and colleagues identified a tumor-promoting role of METTL3 independent of m⁶A reader proteins and its methyltransferase activity. In lung cancer cells, global m⁶A profiling by methylated RNA-immunoprecipitation sequencing revealed m⁶A peaks near the stop codon in mRNAs of multiple oncogenes including EGFR and TAZ, but not others such as MYC and HRAS, and cross-linking immunoprecipitation showed that METTL3 bound to the m⁶A peak within EGFR mRNA. Depletion of METTL3 had little effect on global mRNA levels, but specifically reduced protein levels of EGFR and TAZ, without affecting MYC and RAS levels. Further, METTL3 was detected in polysome fractions, and METTL3 knockdown altered the polysome profile. These findings suggest that METTL3 specifically regulates translation of a subset of m⁶A-containing mRNAs. Accordingly, METTL3 was located in the cytoplasm where protein translation occurs, whereas METTL3 interacting proteins were restricted to the nucleus, suggesting that METTL3 itself promotes translation independent of m⁶A reader proteins. Instead, METTL3 interacted with components of the eIF3 translation initiation complex to promote translation of target mRNAs. The METTL3-dependent increase in translation of several oncogenes suggested a role in cancer, and analysis of data from The Cancer Genome Atlas revealed that METTL3 mRNA was upregulated in lung and colon adenocarcinomas. Lung cancer cell lines exhibited elevated METTL3 protein expression, and METTL3 depletion reduced cell growth and invasive ability, and increased apoptosis. Altogether, these results describe a role for METTL3 in promoting translation of a subset of oncogenes and suggest that it might be a therapeutic target in cancer.

Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m⁶A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell 2016;62:335–45.

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