title: Transcriptome-wide characterization of the eIF4A  signature highlights plasticity in translation  regulation.
abstract: BACKGROUND
  Protein synthesis is tightly regulated and alterations to translation are characteristic of many cancers.Translation regulation is largely exerted at initiation through the eukaryotic translation initiation factor 4 F (eIF4F). eIF4F is pivotal for oncogenic signaling as it integrates mitogenic signals to amplify production of pro-growth and pro-survival factors. Convergence of these signals on eIF4F positions this factor as a gatekeeper of malignant fate. While the oncogenic properties of eIF4F have been characterized, genome-wide evaluation of eIF4F translational output is incomplete yet critical for developing novel translation-targeted therapies.
  
  
  RESULTS
  To understand the impact of eIF4F on malignancy, we utilized a genome-wide ribosome profiling approach to identify eIF4F-driven mRNAs in MDA-MB-231 breast cancer cells. Using Silvestrol, a selective eIF4A inhibitor, we identify 284 genes that rely on eIF4A for efficient translation. Our screen confirmed several known eIF4F-dependent genes and identified many unrecognized targets of translation regulation. We show that 5′UTR complexity determines Silvestrol-sensitivity and altering 5′UTR structure modifies translational output. We highlight physiological implications of eIF4A inhibition, providing mechanistic insight into eIF4F pro-oncogenic activity.
  
  
  CONCLUSIONS
  Here we describe the transcriptome-wide consequence of eIF4A inhibition in malignant cells, define mRNA features that confer eIF4A dependence, and provide genetic support for Silvestrol’s anti-oncogenic properties. Importantly, our results show that eIF4A inhibition alters translation of an mRNA subset distinct from those affected by mTOR-mediated eIF4E inhibition. These results have significant implications for therapeutically targeting translation and underscore a dynamic role for eIF4F in remodeling the proteome toward malignancy.
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608-2916, USA.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Rubio
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weisburd
authors.forename: Matthew
authors.initials: M
authors.lastname: Holderfield
authors.forename: Carolina
authors.initials: C
authors.lastname: Arias
authors.forename: Eric
authors.initials: E
authors.lastname: Fang
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
authors.forename: Abdallah
authors.initials: A
authors.lastname: Fanidi
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects*; D014315:Triterpenes / Q000494:pharmacology; D001572:Benzofurans
chemical_list: D053487:DEAD-box RNA Helicases; D039601:Eukaryotic Initiation Factor-4A; D012333:RNA, Messenger; D014315:Triterpenes; C489897:silvestrol; D001572:Benzofurans; C403493:EIF4A3 protein, human