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

Andrew L. Wolfe, Kamini Singh (), Yi Zhong, Philipp Drewe, Vinagolu K. Rajasekhar, Viraj R. Sanghvi, Konstantinos J. Mavrakis, Man Jiang, Justine E. Roderick, Joni Van der Meulen, Jonathan H. Schatz, Christina M. Rodrigo, Chunying Zhao, Pieter Rondou, Elisa de Stanchina, Julie Teruya-Feldstein, Michelle A. Kelliher, Frank Speleman, John A. Porco, Jerry Pelletier, Gunnar Rätsch () and Hans-Guido Wendel ()
Additional contact information
Andrew L. Wolfe: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Yi Zhong: Memorial Sloan-Kettering Cancer Center
Philipp Drewe: Memorial Sloan-Kettering Cancer Center
Vinagolu K. Rajasekhar: Stem Cell Center and Developmental Biology Program, Memorial Sloan-Kettering Cancer Center
Viraj R. Sanghvi: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Konstantinos J. Mavrakis: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Man Jiang: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Justine E. Roderick: University of Massachusetts Medical School
Joni Van der Meulen: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Jonathan H. Schatz: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Christina M. Rodrigo: Center for Chemical Methodology and Library Development, Boston University
Chunying Zhao: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center
Pieter Rondou: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
Elisa de Stanchina: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center
Julie Teruya-Feldstein: Memorial Sloan-Kettering Cancer Center
Michelle A. Kelliher: University of Massachusetts Medical School
Frank Speleman: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
John A. Porco: Center for Chemical Methodology and Library Development, Boston University
Jerry Pelletier: McGill University, Montreal, Quebec H3G 1Y6, Canada
Gunnar Rätsch: Memorial Sloan-Kettering Cancer Center
Hans-Guido Wendel: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center

Nature, 2014, vol. 513, issue 7516, 65-70

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature13485

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