1. Cancer Biology
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eIF4E S209 phosphorylation licenses Myc-and stress-driven oncogenesis

  1. Hang Ruan
  2. Xiangyun Li
  3. Xiang Xu
  4. Brian J Leibowitz
  5. Jingshan Tong
  6. Lujia Chen
  7. Luoquan Ao
  8. Wei Xing
  9. Jianhua Luo
  10. Yanping Yu
  11. Robert E Schoen
  12. Nahum Sonenberg
  13. Xinghua Lu
  14. Lin Zhang
  15. Jian Yu  Is a corresponding author
  1. University of Pittsburgh, United States
  2. Daping Hospital, China
  3. McGill University, Canada
Research Article
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Cite this article as: eLife 2020;9:e60151 doi: 10.7554/eLife.60151

Abstract

To better understand a role of eIF4E S209 in oncogenic translation, we generated EIF4ES209A/+ heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little on total eIF4E levels, cap binding or global translation, while markedly reduced HCT 116 cell growth in spheroids and mice, and CRC organoid growth. 4EKI strongly inhibited Myc and ATF4 translation, the integrated Stress Response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. 4EKI inhibited polyposis in ApcMin/+ mice by suppressing Myc protein and AKT activation. Furthermore, p-eIF4E was highly elevated in CRC precursor lesions in mouse and human. p-eIF4E cooperated with mutant KRAS to promote Myc and ISR-dependent glutamine addiction in various CRC cell lines, characterized by increased cell death, transcriptomic heterogeneity and immune suppression upon deprivation. These findings demonstrate a critical role of eIF4E S209-dependent translation in Myc and stress-driven oncogenesis and as a potential therapeutic vulnerability.

Article and author information

Author details

  1. Hang Ruan

    Pathology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  2. Xiangyun Li

    Pathology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  3. Xiang Xu

    Stem Cell and Regenerative Medicine, Daping Hospital, Chongqing, China
    Competing interests
    No competing interests declared.
  4. Brian J Leibowitz

    Pathology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  5. Jingshan Tong

    Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  6. Lujia Chen

    Medical Informatics, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  7. Luoquan Ao

    Stem Cell and Regenerative Medicine, Daping Hospital, Chongqing, China
    Competing interests
    No competing interests declared.
  8. Wei Xing

    Stem Cell and Regenerative Medicine, Daping Hospital, Chongqing, China
    Competing interests
    No competing interests declared.
  9. Jianhua Luo

    Pathology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  10. Yanping Yu

    Pathology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  11. Robert E Schoen

    Medicine, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  12. Nahum Sonenberg

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    Nahum Sonenberg, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4707-8759
  13. Xinghua Lu

    Biomedical Informatics, University of Pittsburgh, Pittsbrugh, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8599-2269
  14. Lin Zhang

    Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  15. Jian Yu

    Pathology, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    yuj2@upmc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4021-1000

Funding

NIH (R01CA215481)

  • Jian Yu

NIH (R01CA172136)

  • Lin Zhang

NIH (R01CA203028)

  • Lin Zhang

NIH (R01CA236271)

  • Lin Zhang

NIH (R01LM012011)

  • Xinghua Lu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (# 19085635 and 18063020) of the University of Pittsburgh. All animal experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee under Animal welfare assurance number A-3187-01. No surgery or invasive procedure was performed and every effort was made to minimize suffering with humane sacrifice.

Reviewing Editor

  1. Wafik S El-Deiry, Brown University, United States

Publication history

  1. Received: June 17, 2020
  2. Accepted: October 31, 2020
  3. Accepted Manuscript published: November 2, 2020 (version 1)
  4. Version of Record published: November 13, 2020 (version 2)

Copyright

© 2020, Ruan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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