The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/29830 |
| _version_ | 1811181385606496256 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hiba Ahmad Zahreddine |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:16:51Z |
| format | Article |
| id | doaj.art-347003db749b4cfea541aa4f5080caa2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:16:51Z |
| publishDate | 2017-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-347003db749b4cfea541aa4f5080caa22022-12-22T04:32:18ZengeLife Sciences Publications LtdeLife2050-084X2017-11-01610.7554/eLife.29830The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activityHiba Ahmad Zahreddine0https://orcid.org/0000-0001-8905-1661Biljana Culjkovic-Kraljacic1Audrey Emond2Filippa Pettersson3Ronald Midura4Mark Lauer5Sonia Del Rincon6Valbona Cali7Sarit Assouline8Wilson H Miller9Vincent Hascall10Katherine LB Borden11https://orcid.org/0000-0003-2188-5074Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Québec, CanadaDepartment of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Québec, CanadaSegal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, CanadaSegal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, CanadaOrthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United StatesOrthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United StatesSegal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, CanadaOrthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United StatesSegal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, CanadaSegal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Québec, CanadaOrthopaedic Research Center, The Cleveland Clinic Foundation, Cleveland, United States; Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, United StatesDepartment of Pathology and Cell Biology, Institute for Research in Immunology and Cancer, Université de Montréal, Québec, CanadaThe 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.https://elifesciences.org/articles/29830cell culturePrimary AML SamplesMouse Lung Metastasis |
| spellingShingle | 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 The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity eLife cell culture Primary AML Samples Mouse Lung Metastasis |
| title | The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity |
| title_full | The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity |
| title_fullStr | The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity |
| title_full_unstemmed | The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity |
| title_short | The eukaryotic translation initiation factor eIF4E harnesses hyaluronan production to drive its malignant activity |
| title_sort | eukaryotic translation initiation factor eif4e harnesses hyaluronan production to drive its malignant activity |
| topic | cell culture Primary AML Samples Mouse Lung Metastasis |
| url | https://elifesciences.org/articles/29830 |
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