The Eukaryotic Translation Initiation Factor EIF4E Harnesses Hyaluronan Production to Drive Its Malignant Activity

Overview

Journal Elife

Specialty Biology

Date 2017 Nov 8

PMID 29111978

Citations 13

Authors

Hiba Ahmad Zahreddine

Biljana Culjkovic-Kraljacic

Audrey Emond

Filippa Pettersson

Ronald Midura

Mark Lauer

Sonia Del Rincon

Valbona Cali

Sarit Assouline

Wilson H Miller

Vincent Hascall

Katherine Lb Borden

Affiliations

Soon will be listed here.

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.

Citing Articles

eIF4E orchestrates mRNA processing, RNA export and translation to modify specific protein production.

Mars J, Culjkovic-Kraljacic B, Borden K Nucleus. 2024; 15(1):2360196.

PMID: 38880976 PMC: 11185188. DOI: 10.1080/19491034.2024.2360196.

The eukaryotic translation initiation factor eIF4E unexpectedly acts in splicing thereby coupling mRNA processing with translation: eIF4E induces widescale splicing reprogramming providing system-wide connectivity between splicing, nuclear mRNA....

Borden K Bioessays. 2023; 46(1):e2300145.

PMID: 37926700 PMC: 11021180. DOI: 10.1002/bies.202300145.

Molecular targeting of the UDP-glucuronosyltransferase enzymes in high-eukaryotic translation initiation factor 4E refractory/relapsed acute myeloid leukemia patients: a randomized phase II trial of vismodegib, ribavirin with or without decitabine.

Assouline S, Gasiorek J, Bergeron J, Lambert C, Culjkovic-Kraljacic B, Cocolakis E Haematologica. 2023; 108(11):2946-2958.

PMID: 36951168 PMC: 10620574. DOI: 10.3324/haematol.2023.282791.

The eukaryotic translation initiation factor eIF4E reprograms alternative splicing.

Ghram M, Morris G, Culjkovic-Kraljacic B, Mars J, Gendron P, Skrabanek L EMBO J. 2023; 42(7):e110496.

PMID: 36843541 PMC: 10068332. DOI: 10.15252/embj.2021110496.

Cancer cells hijack RNA processing to rewrite the message.

Borden K Biochem Soc Trans. 2022; 50(5):1447-1456.

PMID: 36282006 PMC: 9704515. DOI: 10.1042/BST20220621.

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