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

• Published in: Nature (London) Vol. 513; no. 7516; pp. 65 - 70
• Main Authors: Wolfe, Andrew L., Singh, Kamini, Zhong, Yi, Drewe, Philipp, Rajasekhar, Vinagolu K., Sanghvi, Viraj R., Mavrakis, Konstantinos J., Jiang, Man, Roderick, Justine E., Van der Meulen, Joni, Schatz, Jonathan H., Rodrigo, Christina M., Zhao, Chunying, Rondou, Pieter, de Stanchina, Elisa, Teruya-Feldstein, Julie, Kelliher, Michelle A., Speleman, Frank, Porco, John A., Pelletier, Jerry, Rätsch, Gunnar, Wendel, Hans-Guido
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.09.2014; Nature Publishing Group
• Subjects: 13/31; 13/44; 13/51; 13/89; 38; 38/39; 38/90; 38/91; 45; 5' Untranslated Regions - genetics; 631/67/1059; 631/67/1990/283/2125; 631/67/68; 631/80/83/2359; 64/60; 96; 96/106; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Base Sequence; Cancer; Cell Line, Tumor; Epigenesis, Genetic; Eukaryotic Initiation Factor-4A - metabolism; Female; G-Quadruplexes; Genetic aspects; Genetic research; Genetic translation; Humanities and Social Sciences; Humans; Kinases; Leukemia; Mice; Mice, Inbred C57BL; MicroRNAs; multidisciplinary; Mutation; Nucleotide Motifs; Oncogene Proteins - biosynthesis; Oncogene Proteins - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Protein Biosynthesis - drug effects; Proteins; Ribosomes - metabolism; RNA sequencing; Science; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Triterpenes - pharmacology
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature13485

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. The translation of many messenger RNAs that encode important oncogenes and transcription factors depends on the eIF4A RNA helicase to resolve G-quadruplex structures, implying eIF4A inhibition as an effective cancer therapy. eIF4F interaction with oncoproteins The expression of some oncoproteins is regulated at the translational level. Hans-Guido Wendel and colleagues show that a subset of oncoprotein- and transcription factor-encoding mRNAs that are dependent on the translation initiation factor eIF4A contain a G-quadruplex-forming structure in their 5′ untranslated regions. These findings explain why silvestrol, a plant-derived anticancer agent that targets eIF4A-dependent translation, is not generally toxic but can be well tolerated except in cancer cells which are dependent on the activities of these proteins. In a separate study in this issue, Stéphan Vagner and colleagues show that inhibition of eIF4F cooperates with BRAF inhibitors in reducing the growth of melanomas linked to BRAF mutations.