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

Andrew L. Wolfe, Kamini Singh, Y. 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 PelletierGunnar Rätsch, Hans Guido Wendel

Research output: Contribution to journalArticle

215 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)65-70
Number of pages6
JournalNature
Volume513
Issue number7516
DOIs
StatePublished - 2014

Fingerprint

G-Quadruplexes
Oncogenes
RNA Helicases
5' Untranslated Regions
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms
Neoplasm Genes
Oncogene Proteins
Therapeutic Uses
Ribosomes
Transcriptome
Epigenomics
Carcinogenesis
Leukemia
Transcription Factors
Nucleotides
Maintenance
silvestrol

ASJC Scopus subject areas

  • General

Cite this

Wolfe, A. L., Singh, K., Zhong, Y., Drewe, P., Rajasekhar, V. K., Sanghvi, V. R., ... Wendel, H. G. (2014). RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature, 513(7516), 65-70. https://doi.org/10.1038/nature13485

RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. / Wolfe, Andrew L.; Singh, Kamini; Zhong, Y.; 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.

In: Nature, Vol. 513, No. 7516, 2014, p. 65-70.

Research output: Contribution to journalArticle

Wolfe, AL, Singh, K, Zhong, Y, Drewe, P, Rajasekhar, VK, Sanghvi, VR, Mavrakis, KJ, Jiang, M, Roderick, JE, Van der Meulen, J, Schatz, JH, Rodrigo, CM, Zhao, C, Rondou, P, de Stanchina, E, Teruya-Feldstein, J, Kelliher, MA, Speleman, F, Porco, JA, Pelletier, J, Rätsch, G & Wendel, HG 2014, 'RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.', Nature, vol. 513, no. 7516, pp. 65-70. https://doi.org/10.1038/nature13485
Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature. 2014;513(7516):65-70. https://doi.org/10.1038/nature13485
Wolfe, Andrew L. ; Singh, Kamini ; Zhong, Y. ; 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. / RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. In: Nature. 2014 ; Vol. 513, No. 7516. pp. 65-70.
@article{b4fd6d90ae724434bdef122d1b6cb2cc,
title = "RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.",
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.",
author = "Wolfe, {Andrew L.} and Kamini Singh and Y. Zhong and Philipp Drewe and Rajasekhar, {Vinagolu K.} and Sanghvi, {Viraj R.} and Mavrakis, {Konstantinos J.} and Man Jiang and Roderick, {Justine E.} and {Van der Meulen}, Joni and Schatz, {Jonathan H} and Rodrigo, {Christina M.} and Chunying Zhao and Pieter Rondou and {de Stanchina}, Elisa and Julie Teruya-Feldstein and Kelliher, {Michelle A.} and Frank Speleman and Porco, {John A.} and Jerry Pelletier and Gunnar R{\"a}tsch and Wendel, {Hans Guido}",
year = "2014",
doi = "10.1038/nature13485",
language = "English (US)",
volume = "513",
pages = "65--70",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7516",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84907221438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907221438&partnerID=8YFLogxK

U2 - 10.1038/nature13485

DO - 10.1038/nature13485

M3 - Article

C2 - 25079319

AN - SCOPUS:84907221438

VL - 513

SP - 65

EP - 70

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7516

ER -