1. Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation
- Author
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Rubio, Claudia A, Weisburd, Benjamin, Holderfield, Matthew, Arias, Carolina, Fang, Eric, DeRisi, Joseph L, and Fanidi, Abdallah
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Cancer ,Human Genome ,Genetics ,Prevention ,Apoptosis ,Cell Cycle Checkpoints ,Cell Line ,Tumor ,DEAD-box RNA Helicases ,Eukaryotic Initiation Factor-4A ,Gene Expression Regulation ,Neoplastic ,Humans ,Protein Biosynthesis ,RNA ,Messenger ,Transcriptome ,Triterpenes ,Environmental Sciences ,Information and Computing Sciences ,Bioinformatics - Abstract
BackgroundProtein 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.ResultsTo 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.ConclusionsHere 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.
- Published
- 2014