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.
authors: 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA [3].
authors: Andrew L
authors: AL
authors: Wolfe
authors: 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2].
authors: Kamini
authors: K
authors: Singh
authors: Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Yi
authors: Y
authors: Zhong
authors: Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Philipp
authors: P
authors: Drewe
authors: Stem Cell Center and Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Vinagolu K
authors: VK
authors: Rajasekhar
authors: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Viraj R
authors: VR
authors: Sanghvi
authors: 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.).
authors: Konstantinos J
authors: KJ
authors: Mavrakis
authors: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Man
authors: M
authors: Jiang
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 USA.
authors: Justine E
authors: JE
authors: Roderick
authors: 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Joni
authors: J
authors: Van der Meulen
authors: 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.).
authors: Jonathan H
authors: JH
authors: Schatz
authors: Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, Boston, Massachusetts 02215, USA.
authors: Christina M
authors: CM
authors: Rodrigo
authors: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Chunying
authors: C
authors: Zhao
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Pieter
authors: P
authors: Rondou
authors: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Elisa
authors: E
authors: de Stanchina
authors: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Julie
authors: J
authors: Teruya-Feldstein
authors: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 USA.
authors: Michelle A
authors: MA
authors: Kelliher
authors: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors: Frank
authors: F
authors: Speleman
authors: Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, Boston, Massachusetts 02215, USA.
authors: John A
authors: JA
authors: Porco
authors: 1] Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada [2] Department of Oncology, McGill University, Montreal, Quebec H3G 1Y6, Canada [3] The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors: Jerry
authors: J
authors: Pelletier
authors: Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Gunnar
authors: G
authors: Rätsch
authors: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Hans-Guido
authors: HG
authors: Wendel
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism*; D005260:Female; D054856:G-Quadruplexes; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D059372:Nucleotide Motifs; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D012270:Ribosomes / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014315:Triterpenes / Q000494:pharmacology; D001572:Benzofurans
chemical_list: D020121:5' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic; D039601:Eukaryotic Initiation Factor-4A; D015513:Oncogene Proteins; D014157:Transcription Factors; D014315:Triterpenes; C489897:silvestrol; D001572:Benzofurans