The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity
- Université de Montréal, Canada
- Jewish General Hospital, Canada
- Cleveland Clinic Foundation, United States
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.
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Author details
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.
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.
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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The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity
eLife 6:e29830.
https://doi.org/10.7554/eLife.29830
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