title: Differential Regulation of the Melanoma Proteome by eIF4A1 and eIF4E.
abstract: Small molecules and antisense oligonucleotides that inhibit the translation initiation factors eIF4A1 and eIF4E have been explored as broad-based therapeutic agents for cancer treatment, based on the frequent upregulation of these two subunits of the eIF4F cap-binding complex in many cancer cells. Here, we provide support for these therapeutic approaches with mechanistic studies of eIF4F-driven tumor progression in a preclinical model of melanoma. Silencing eIF4A1 or eIF4E decreases melanoma proliferation and invasion. There were common effects on the level of cell-cycle proteins that could explain the antiproliferative effects in vitro Using clinical specimens, we correlate the common cell-cycle targets of eIF4A1 and eIF4E with patient survival. Finally, comparative proteomic and transcriptomic analyses reveal extensive mechanistic divergence in response to eIF4A1 or eIF4E silencing. Current models indicate that eIF4A1 and eIF4E function together through the 5'UTR to increase translation of oncogenes. In contrast, our data demonstrate that the common effects of eIF4A1 and eIF4E on translation are mediated by the coding region and 3'UTR. Moreover, their divergent effects occur through the 5'UTR. Overall, our work shows that it will be important to evaluate subunit-specific inhibitors of eIF4F in different disease contexts to fully understand their anticancer actions. Cancer Res; 77(3); 613-22. ©2016 AACR.
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Cailin E
authors.initials: CE
authors.lastname: Joyce
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Adrienne G
authors.initials: AG
authors.lastname: Yanez
authors.affiliation: Program in Systems Biology and Program in Molecular Medicine, University of Massachusetts, Worcester, Massachusetts.|Onami team, The Systems Biology Institute, Tokyo, Japan.|Laboratory for Developmental Dynamics, RIKEN Quantitative Biology Center, Hyogo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mori
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Johanna S
authors.initials: JS
authors.lastname: Carroll
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts. carl_novina@dfci.harvard.edu.|Department of Medicine, Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Novina
mesh_terms: D045744:Cell Line, Tumor; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D013058:Mass Spectrometry; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D020543:Proteome; D040901:Proteomics; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D039562:Eukaryotic Initiation Factor-4F; D020543:Proteome