RNA G-quadruplexes Cause EIF4A-dependent Oncogene Translation in Cancer

Overview

Journal Nature

Specialty Science

Date 2014 Aug 1

PMID 25079319

Citations 345

Authors

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 Jr

Jerry Pelletier

Gunnar Ratsch

Hans-Guido Wendel

Affiliations

Soon will be listed here.

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.

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References

Chakraborty P, Grosse F . Human DHX9 helicase preferentially unwinds RNA-containing displacement loops (R-loops) and G-quadruplexes. DNA Repair (Amst). 2011; 10(6):654-65. DOI: 10.1016/j.dnarep.2011.04.013. View

Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden K . Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci U S A. 2004; 101(52):18105-10. PMC: 539790. DOI: 10.1073/pnas.0406927102. View

Hofacker I . Vienna RNA secondary structure server. Nucleic Acids Res. 2003; 31(13):3429-31. PMC: 169005. DOI: 10.1093/nar/gkg599. View

Zenatti P, Ribeiro D, Li W, Zuurbier L, Silva M, Paganin M . Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011; 43(10):932-9. PMC: 7424552. DOI: 10.1038/ng.924. View

Parsyan A, Svitkin Y, Shahbazian D, Gkogkas C, Lasko P, Merrick W . mRNA helicases: the tacticians of translational control. Nat Rev Mol Cell Biol. 2011; 12(4):235-45. DOI: 10.1038/nrm3083. View

Flicek P, Ahmed I, Amode M, Barrell D, Beal K, Brent S . Ensembl 2013. Nucleic Acids Res. 2012; 41(Database issue):D48-55. PMC: 3531136. DOI: 10.1093/nar/gks1236. View

Moerke N, Aktas H, Chen H, Cantel S, Reibarkh M, Fahmy A . Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell. 2007; 128(2):257-67. DOI: 10.1016/j.cell.2006.11.046. View

Weng A, Millholland J, Yashiro-Ohtani Y, Arcangeli M, Lau A, Wai C . c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 2006; 20(15):2096-109. PMC: 1536060. DOI: 10.1101/gad.1450406. View

Shochat C, Tal N, Bandapalli O, Palmi C, Ganmore I, Te Kronnie G . Gain-of-function mutations in interleukin-7 receptor-α (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med. 2011; 208(5):901-8. PMC: 3092356. DOI: 10.1084/jem.20110580. View

10.

Penn L, Brooks M, Laufer E, Land H . Negative autoregulation of c-myc transcription. EMBO J. 1990; 9(4):1113-21. PMC: 551786. DOI: 10.1002/j.1460-2075.1990.tb08217.x. View

11.

Bordeleau M, Robert F, Gerard B, Lindqvist L, Chen S, Wendel H . Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008; 118(7):2651-60. PMC: 2423864. DOI: 10.1172/JCI34753. View

12.

Bugaut A, Balasubramanian S . 5'-UTR RNA G-quadruplexes: translation regulation and targeting. Nucleic Acids Res. 2012; 40(11):4727-41. PMC: 3367173. DOI: 10.1093/nar/gks068. View

13.

Thoreen C, Chantranupong L, Keys H, Wang T, Gray N, Sabatini D . A unifying model for mTORC1-mediated regulation of mRNA translation. Nature. 2012; 485(7396):109-13. PMC: 3347774. DOI: 10.1038/nature11083. View

14.

Montine K, Sonenberg N . Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap. Nature. 1990; 345(6275):544-7. DOI: 10.1038/345544a0. View

15.

Shahid R, Bugaut A, Balasubramanian S . The BCL-2 5' untranslated region contains an RNA G-quadruplex-forming motif that modulates protein expression. Biochemistry. 2010; 49(38):8300-6. PMC: 3038430. DOI: 10.1021/bi100957h. View

16.

Pear W, Aster J, Scott M, Hasserjian R, Soffer B, Sklar J . Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996; 183(5):2283-91. PMC: 2192581. DOI: 10.1084/jem.183.5.2283. View

17.

Rong L, Livingstone M, Sukarieh R, Petroulakis E, Gingras A, Crosby K . Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs. RNA. 2008; 14(7):1318-27. PMC: 2441981. DOI: 10.1261/rna.950608. View

18.

Huppert J, Bugaut A, Kumari S, Balasubramanian S . G-quadruplexes: the beginning and end of UTRs. Nucleic Acids Res. 2008; 36(19):6260-8. PMC: 2577360. DOI: 10.1093/nar/gkn511. View

19.

Mavrakis K, Zhu H, Silva R, Mills J, Teruya-Feldstein J, Lowe S . Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev. 2008; 22(16):2178-88. PMC: 2518821. DOI: 10.1101/gad.1690808. View

20.

Menten B, Pattyn F, De Preter K, Robbrecht P, Michels E, Buysse K . arrayCGHbase: an analysis platform for comparative genomic hybridization microarrays. BMC Bioinformatics. 2005; 6:124. PMC: 1173083. DOI: 10.1186/1471-2105-6-124. View