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PMID: 27117702 Published · ppublish English Journal Article

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

Molecular cell ·Vol. 62 ·No. 3 ·2016-00-05 ·Pages 335-345

Lin S, Choe J, Du P, Triboulet R, Gregory RI

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,genetics,pathology Adenocarcinoma of Lung Cell Movement Cell Proliferation Cell Survival ErbB Receptors/biosynthesis,genetics Eukaryotic Initiation Factor-3/metabolism Gene Expression Regulation, Neoplastic Humans Intracellular Signaling Peptides and Proteins/biosynthesis,genetics Lung Neoplasms/enzymology,genetics,pathology Methyltransferases/genetics,metabolism Neoplasm Invasiveness Peptide Chain Initiation, Translational RNA Interference RNA, Messenger/genetics,metabolism Ribosomes/enzymology Signal Transduction Trans-Activators Transcription Factors Transcriptional Coactivator with PDZ-Binding Motif Proteins Transfection Up-Regulation
Chemicals
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
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lin Shuibin
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.
Choe Junho
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.
Du Peng
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.
Triboulet Robinson
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.
Gregory Richard I
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.
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2016.03.021
Email
rgregory@enders.tch.harvard.edu
Published
2016-00-05
Epub
2016-00-21
Pages
335-345
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC4860043
Subset
IM
Grants
NIGMS NIH HHS · P01 GM099117 · United States
NIGMS NIH HHS · R01 GM086386 · United States
Corrections
CommentIn
PMID: 27153530
External Links
PubMed source DOI: 10.1016/j.molcel.2016.03.021 PMC Full Text View journal details
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