[en] Quantitative and qualitative changes in mRNA translation occur in tumor cells and support cancer progression and metastasis. Post-transcriptional nucleoside modifications of transfer RNAs (tRNAs) at the wobble U34 base are highly conserved and contribute to translation fidelity. Here, we show that ELP3 and CTU1/2, partner enzymes in U34 mcm5s2-tRNA modification, are upregulated 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 pro-invasive transcription factor LEF1. Consistently, a DEK mutant, whose codon composition is independent of U34 mcm5s2-tRNA modification, escapes the ELP3- and CTU1-dependent regulation and restores the IRES-dependent LEF1 expression. Our results demonstrate the key role of U34 tRNA modification 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.
Research center :
GIGA Molecular Biology of Diseases - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Delaunay, Sylvain ; Université de Liège > Département de pharmacie > Chimie médicale
Rapino, Francesca ; Université de Liège > Département de pharmacie > Chimie médicale
Tharun, Lars
Zhou, Zhaoli ; Université de Liège > Département de pharmacie > Chimie médicale
Heukamp, Lukas
Termathe, M
Shostak, Kateryna ; Université de Liège > Département de pharmacie > Chimie médicale
Klevernic, Iva ; Université de Liège > Département de pharmacie > Chimie médicale
ELP3 links tRNA modification to IRES-dependent translation of LEF-1 to promote metastasis in breast cancer
Publication date :
October 2016
Journal title :
Journal of Experimental Medicine
ISSN :
0022-1007
eISSN :
1540-9538
Publisher :
The Rockfeller University press, United States
Volume :
213
Pages :
2503-2523
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
WELBIO - Institut wallon virtuel de recherche d'excellence dans les domaines des sciences de la vie [BE] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Télévie [BE]
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