The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells

Mol Cell. 2016 May 5;62(3):335-345. doi: 10.1016/j.molcel.2016.03.021. Epub 2016 Apr 21.

Abstract

METTL3 is an RNA methyltransferase implicated in mRNA biogenesis, decay, and translation control through N(6)-methyladenosine (m(6)A) 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 m(6)A 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.

Keywords: EGFR; METTL3; N(6)-methyladenosine; cancer; m(6)A; ribosome; translation.

MeSH terms

  • A549 Cells
  • Adenocarcinoma / enzymology*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics
  • Eukaryotic Initiation Factor-3 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / biosynthesis
  • Intracellular Signaling Peptides and Proteins / genetics
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Neoplasm Invasiveness
  • Peptide Chain Initiation, Translational*
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Ribosomes / enzymology
  • Signal Transduction
  • Transcription Factors
  • Transfection
  • Up-Regulation

Substances

  • Eukaryotic Initiation Factor-3
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Transcription Factors
  • WWTR1 protein, human
  • Methyltransferases
  • METTL3 protein, human
  • EGFR protein, human
  • ErbB Receptors