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

Shuibin Lin; Junho Choe; Peng Du; Robinson Triboulet; Richard I Gregory

doi:10.1016/j.molcel.2016.03.021

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.

Authors

Shuibin Lin¹, Junho Choe¹, Peng Du¹, Robinson Triboulet¹, Richard I Gregory²

Affiliations

¹ Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
² Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: rgregory@enders.tch.harvard.edu.

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
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Transfection
Up-Regulation

Substances

Eukaryotic Initiation Factor-3
Intracellular Signaling Peptides and Proteins
RNA, Messenger
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
WWTR1 protein, human
Methyltransferases
METTL3 protein, human
EGFR protein, human
ErbB Receptors

Abstract

MeSH terms

Substances

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