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Nature. 2014 Sep 4;513(7516):65-70. doi: 10.1038/nature13485. Epub 2014 Jul 27.

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.

Author information

1
1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA [3].
2
1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2].
3
Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
4
Stem Cell Center and Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
5
Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
6
1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.).
7
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 USA.
8
1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
9
1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.).
10
Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, Boston, Massachusetts 02215, USA.
11
Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
12
Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
13
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
14
1] Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada [2] Department of Oncology, McGill University, Montreal, Quebec H3G 1Y6, Canada [3] The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6, Canada.

Abstract

The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

PMID:
25079319
PMCID:
PMC4492470
DOI:
10.1038/nature13485
[Indexed for MEDLINE]
Free PMC Article

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