Abstract
eIF4A is required for the translation of transcripts with 5′ UTRs that can form G-quadruplexes.
Major finding: eIF4A is required for the translation of transcripts with 5′ UTRs that can form G-quadruplexes.
Concept: Subsets of mRNAs can be translationally regulated, for example in an eIF4A-dependent manner.
Impact: Blockade of oncoprotein translation through inhibition of eIF4A may be an effective therapeutic strategy.
Eukaryotic initiation factor 4A (eIF4A) is a component of the translation initiation complex required for 5′ cap-dependent translation initiation. eIF4A has RNA helicase activity that contributes to locating translation start sites within 5′ untranslated regions (UTR) of mRNA transcripts, but the role of eIF4A in translational regulation and the features of eIF4A helicase-dependent transcripts remain unclear. Wolfe, Singh, and colleagues found that eIF4A overexpression accelerated Notch1-mutant or Pten-null leukemia development in vivo and that inhibition of eIF4A with the natural compound silvestrol had antileukemic activity in vitro and in vivo. Using ribosome footprinting, a method where ribosome-protected RNA fragments are identified by deep sequencing, to identify and characterize eIF4A-dependent transcripts affected by silvestrol treatment in T-ALL cells, the authors found that eIF4A inhibition selectively reduced the translational efficiency of transcripts with long 5′ UTRs, particularly those with a 12-nucleotide (CGG)4 motif and other guanine-rich motifs computationally predicted to form four-stranded structures known as G-quadruplexes through non-Watson–Crick interactions. In vitro, silvestrol specifically reduced the translation of a G-quadruplex reporter construct but not a control construct, further suggesting that eIF4A is needed for the translation of complex 5′ UTRs. Interestingly, silvestrol-sensitive transcripts included those of known T-ALL driver genes, such as MYC, NOTCH1, RUNX1, and BCL2, and were enriched for superenhancer-associated genes. Silvestrol markedly reduced protein levels of many oncogenes and transcription factors in T-ALL cells in vitro and in vivo, and expression of MYC and BCL2 under the control of an eIF4A-independent internal ribosomal entry site protected murine T-ALL cells from the effects of silvestrol, providing further evidence that silvestrol exerts antitumor activity by simultaneously disrupting the translation of multiple oncogenes and that eIF4A-dependent translation may be an attractive therapeutic target.
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