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

被引：535

作者：

Wolfe, Andrew L. ^{[1
,2
]}

Singh, Kamini ^{[1
]}

Zhong, Yi ^{[3
]}

Drewe, Philipp ^{[3
]}

Rajasekhar, Vinagolu K. ^{[4
,5
]}

Sanghvi, Viraj R. ^{[1
]}

Mavrakis, Konstantinos J. ^{[1
]}

Jiang, Man ^{[1
]}

Roderick, Justine E. ^{[6
]}

Van der Meulen, Joni ^{[1
,7
]}

Schatz, Jonathan H. ^{[1
,8
]}

Rodrigo, Christina M. ^{[9
]}

Zhao, Chunying ^{[1
]}

Rondou, Pieter ^{[7
]}

de Stanchina, Elisa ^{[10
]}

Teruya-Feldstein, Julie ^{[11
]}

Kelliher, Michelle A. ^{[6
]}

Speleman, Frank ^{[7
]}

Porco, John A., Jr. ^{[9
]}

Pelletier, Jerry ^{[12
,13
,14
]}

Raetsch, Gunnar ^{[3
]}

Wendel, Hans-Guido ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA

[2] Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Computat Biol Dept, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Stem Cell Ctr, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA

[6] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA

[7] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium

[8] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[9] Boston Univ, Dept Chem, Ctr Chem Methodol & Lib Dev, Boston, MA 02215 USA

[10] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, New York, NY 10065 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[12] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[13] McGill Univ, Dept Oncol, Montreal, PQ H3G 1Y6, Canada

[14] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada

来源：

NATURE | 2014年 / 513卷 / 7516期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; OF-FUNCTION MUTATIONS; C-MYC; INITIATION; EIF4E; CAP; AKT; TRANSCRIPTION; INHIBITION; MOTIF;

D O I：

10.1038/nature13485

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：65 / +

页数：16

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