Key contribution of eIF4H-mediated translational control in tumor promotion

Charlotte Vaysse, Céline Philippe, Yvan Martineau, Cathy Quelen, Corinne Hieblot, Claire Renaud, Yvan Nicaise, Aurore Desquesnes, Maria Pannese, Thomas Filleron, Ghislaine Escourrou, Malcolm Lawson, Robert C. Rintoul, Marie Bernadette Delisle, Stéphane Pyronnet, Pierre Brousset, Hervé Prats, Christian Touriol

Research output: Contribution to journalArticlepeer-review

Abstract

Dysregulated expression of translation initiation factors has been associated with carcinogenesis, but underlying mechanisms remains to be fully understood. Here we show that eIF4H (eukaryotic translation initiation factor 4H), an activator of the RNA helicase eIF4A, is overexpressed in lung carcinomas and predictive of response to chemotherapy. In lung cancer cells, depletion of eIF4H enhances sensitization to chemotherapy, decreases cell migration and inhibits tumor growth in vivo, in association with reduced translation of mRNA encoding cell-proliferation (c-Myc, cyclin D1) angiogenic (FGF-2) and anti-apoptotic factors (CIAP-1, BCL-xL). Conversely, each isoform of eIF4H acts as an oncogene in NIH3T3 cells by stimulating transformation, invasion, tumor growth and resistance to drug-induced apoptosis together with increased translation of IRES-containing or structured 5'UTR mRNAs. These results demonstrate that eIF4H plays a crucial role in translational control and can promote cellular transformation by preferentially regulating the translation of potent growth and survival factor mRNAs, indicating that eIF4H is a promising new molecular target for cancer therapy.

Original languageEnglish
Pages (from-to)39924-39940
Number of pages17
JournalOncotarget
Volume6
Issue number37
DOIs
Publication statusPublished - 2015

Keywords

  • Chemoresistance
  • EIF4H
  • Helicase
  • IRES
  • Lung carcinoma
  • Translation initiation factor

ASJC Scopus subject areas

  • Oncology

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