Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Québec, Canada
Biljana Culjkovic-Kraljacic
Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Québec, Canada
Audrey Emond
Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, Canada
Filippa Pettersson
Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, Canada
Ronald Midura
Orthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United States
Mark Lauer
Orthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United States
Sonia Del Rincon
Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, Canada
Valbona Cali
Orthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United States
Sarit Assouline
Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, Canada
Wilson H Miller
Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, Canada
Vincent Hascall
Orthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United States
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.
