RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Academic Article uri icon

Overview

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

  • Wolfe, Andrew Lerner
  • Singh, Kamini
  • Zhong, Yi
  • 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

publication date

  • July 27, 2014

Research

keywords

  • 5' Untranslated Regions
  • Eukaryotic Initiation Factor-4A
  • G-Quadruplexes
  • Oncogene Proteins
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Protein Biosynthesis

Identity

PubMed Central ID

  • PMC4492470

Scopus Document Identifier

  • 84907221438

Digital Object Identifier (DOI)

  • 10.1261/rna.033209.112

PubMed ID

  • 25079319

Additional Document Info

volume

  • 513

issue

  • 7516