Elp3 Links TRNA Modification to IRES-dependent Translation of LEF1 to Sustain Metastasis in Breast Cancer

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2016 Nov 5

PMID 27811057

Citations 99

Authors

Sylvain Delaunay

Francesca Rapino

Lars Tharun

Zhaoli Zhou

Lukas Heukamp

Martin Termathe

Kateryna Shostak

Iva Klevernic

Alexandra Florin

Hadrien Desmecht

Christophe J Desmet

Laurent Nguyen

Sebastian A Leidel

Anne E Willis

Reinhard Buttner

Alain Chariot

Pierre Close

Affiliations

Soon will be listed here.

Abstract

Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Posttranscriptional modifications of transfer RNAs (tRNAs) at the wobble uridine 34 (U34) base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcms-tRNA modification, are up-regulated in human breast cancers and sustain metastasis. Elp3 genetic ablation strongly impaired invasion and metastasis formation in the PyMT model of invasive breast cancer. Mechanistically, ELP3 and CTU1/2 support cellular invasion through the translation of the oncoprotein DEK. As a result, DEK promotes the IRES-dependent translation of the proinvasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcms-tRNA modification, escapes the ELP3- and CTU1-dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate that the key role of U34 tRNA modification is to support specific translation during breast cancer progression and highlight a functional link between tRNA modification- and IRES-dependent translation during tumor cell invasion and metastasis.

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