The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity

Abstract

The microenvironment provides a functional substratum supporting tumour growth. Hyaluronan (HA) is a major component of this structure. While the role of HA in malignancy is well-defined, the mechanisms driving its biosynthesis in cancer are poorly understood. We show that the eukaryotic translation initiation factor eIF4E, an oncoprotein, drives HA biosynthesis. eIF4E stimulates production of enzymes that synthesize the building blocks of HA, UDP-Glucuronic acid and UDP-N-Acetyl-Glucosamine, as well as hyaluronic acid synthase which forms the disaccharide chain. Strikingly, eIF4E inhibition alone repressed HA levels as effectively as directly targeting HA with hyaluronidase. Unusually, HA was retained on the surface of high-eIF4E cells, rather than being extruded into the extracellular space. Surface-associated HA was required for eIF4E's oncogenic activities suggesting that eIF4E potentiates an oncogenic HA program. These studies provide unique insights into the mechanisms driving HA production and demonstrate that an oncoprotein can co-opt HA biosynthesis to drive malignancy.

Article and author information

Author details

  1. Hiba Ahmad Zahreddine

    Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Biljana Culjkovic-Kraljacic

    Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Audrey Emond

    Segal Cancer Centre, Jewish General Hospital, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Filippa Pettersson

    Segal Cancer Centre, Jewish General Hospital, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Ronald Midura

    Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Mark Lauer

    Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sonia Del Rincon

    Segal Cancer Centre, Jewish General Hospital, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Valbona Cali

    Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sarit Assouline

    Segal Cancer Centre, Jewish General Hospital, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Wilson H Miller

    Segal Cancer Centre, Jewish General Hospital, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Vincent Hascall

    Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Katherine Borden

    Institute for Research in Immunology, Université de Montréal, Montréal, Canada
    For correspondence
    katherine.borden@umontreal.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2188-5074

Funding

National Institutes of Health

  • Hiba Ahmad Zahreddine
  • Katherine Borden

Leukemia and Lymphoma Society

  • Hiba Ahmad Zahreddine
  • Katherine Borden

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

Reviewing Editor

  1. Alan G. Hinnebusch, National Institutes of Health, United States

Ethics

Human subjects: Written informed consent was obtained in accordance with the Declaration of Helsinki. This study received IRB approval from the Conseil d'évaluation éthique pour les recherches en santé (CERES) (approval numbers 13-089-CERES and 14-112-CERES) and the Comité d'éthique de la faculté de Medicine (CERFM#195; tissue bank). The study was also approved by Health Canada (112878, 132348 and 173149; samples taken from three different protocols). ClinicalTrials.gov registry numbers: NCT00559091, NCT01056523 and NCT02073838.

Version history

  1. Received: June 22, 2017
  2. Accepted: November 3, 2017
  3. Accepted Manuscript published: November 7, 2017 (version 1)
  4. Version of Record published: November 28, 2017 (version 2)

Copyright

© 2017, Zahreddine 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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  1. Hiba Ahmad Zahreddine
  2. Biljana Culjkovic-Kraljacic
  3. Audrey Emond
  4. Filippa Pettersson
  5. Ronald Midura
  6. Mark Lauer
  7. Sonia Del Rincon
  8. Valbona Cali
  9. Sarit Assouline
  10. Wilson H Miller
  11. Vincent Hascall
  12. Katherine Borden
(2017)
The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity
eLife 6:e29830.
https://doi.org/10.7554/eLife.29830

Share this article

https://doi.org/10.7554/eLife.29830

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