TY - JOUR
T1 - RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.
AU - Wolfe, Andrew L.
AU - Singh, Kamini
AU - Zhong, Y.
AU - Drewe, Philipp
AU - Rajasekhar, Vinagolu K.
AU - Sanghvi, Viraj R.
AU - Mavrakis, Konstantinos J.
AU - Jiang, Man
AU - Roderick, Justine E.
AU - Van der Meulen, Joni
AU - Schatz, Jonathan H.
AU - Rodrigo, Christina M.
AU - Zhao, Chunying
AU - Rondou, Pieter
AU - de Stanchina, Elisa
AU - Teruya-Feldstein, Julie
AU - Kelliher, Michelle A.
AU - Speleman, Frank
AU - Porco, John A.
AU - Pelletier, Jerry
AU - Rätsch, Gunnar
AU - Wendel, Hans Guido
N1 - Funding Information:
Acknowledgements We thank the members of A.L.W.’s thesis committee: N. Rosen, A. M. Brown and S. W. Lowe. For reagents and advice we thank J. T. Barata, W. S. Pear, R. Cencic, S. Shuman, J. Cools, A. A. Ferrando, C. S. Fraser, N. J. Lajkiewicz, A. Luz, J. F. Glickman, C. Y. Park, P. Yellen, A. Heguy, K. Huberman and A. Viale. H.-G.W. is a Scholar of the Leukemia and Lymphoma Society. This research was supported by National Cancer Institute R01-CA142798-01 (H.-G.W.), the Leukemia Research Foundation (H.-G.W.), the Experimental Therapeutics Center (H.-G.W.), the American Cancer Society 10284 (H.-G.W.), European Union grant no. PITN-GA-2012-316861 (Y.Z.), the Fund for Scientific Research FWO Flanders (J.V.d.M. and P.R.), grants G.0198.08 and G.0869.10N (F.S.), the GOA-UGent 12051203 (F.S.), Stichting tegen Kanker (F.S.), the Belgian Program of Interuniversity Poles of Attraction (F.S.), the Belgian Foundation Against Cancer (F.S.), the American Cancer Society PF-11-077-01-CDD (C.M.R.), the Lymphoma Research Foundation (J.H.S.), National Institutes of Health grants GM-067041 and GM-073855 (J.A.P.), and the Canadian Institutes of Health Research MOP-10653 (J.P.).
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1038/nature13485
DO - 10.1038/nature13485
M3 - Article
C2 - 25079319
AN - SCOPUS:84907221438
SN - 0028-0836
VL - 513
SP - 65
EP - 70
JO - Nature
JF - Nature
IS - 7516
ER -
