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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.

journal_name

Genome Biol

journal_title

Genome biology

authors

Rubio CA,Weisburd B,Holderfield M,Arias C,Fang E,DeRisi JL,Fanidi A

doi

10.1186/s13059-014-0476-1

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

476

issue

eissn

1474-7596

issn

1474-760X

pii

s13059-014-0476-1

journal_volume

pub_type

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Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation.