Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.
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 mcm5s2-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 mcm5s2-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.
Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Sylvain
0000-0002-8459-6432
S
Delaunay
Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Francesca
F
Rapino
Institute for Pathology, University Hospital Cologne, 50937 Cologne, Germany.
Lars
0000-0001-7375-0775
L
Tharun
Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Zhaoli
0000-0003-4217-2567
Z
Zhou
Institute for Pathology, University Hospital Cologne, 50937 Cologne, Germany.
Lukas
0000-0002-3388-3482
L
Heukamp
Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster.|Faculty of Medicine, University of Muenster, 48129 Muenster, Germany.
Martin
0000-0002-5618-4633
M
Termathe
Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Kateryna
K
Shostak
Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Iva
0000-0003-0919-166X
I
Klevernic
Institute for Pathology, University Hospital Cologne, 50937 Cologne, Germany.
Alexandra
0000-0002-2330-4176
A
Florin
Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Hadrien
H
Desmecht
GIGA-Infection, Immunity and Inflammation, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Christophe J
0000-0002-5723-2449
CJ
Desmet
GIGA-Neurosiences, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Laurent
L
Nguyen
Max Planck Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster.|Faculty of Medicine, University of Muenster, 48129 Muenster, Germany.|Cells-in-Motion Cluster of Excellence, University of Muenster, 48129 Muenster, Germany.
Sebastian A
0000-0002-0523-6325
SA
Leidel
Medical Research Council Toxicology Unit, Leicester LE1 9HN, England, UK.
Anne E
AE
Willis
Institute for Pathology, University Hospital Cologne, 50937 Cologne, Germany.
Reinhard
R
Büttner
Laboratory of Medical Chemistry, University of Liège, 4000 Liège, Belgium Alain.Chariot@ulg.ac.be Pierre.Close@ulg.ac.be.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.|Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1300 Wavre, Belgium.
Alain
0000-0002-1691-4347
A
Chariot
Laboratory of Cancer Signaling, University of Liège, 4000 Liège, Belgium Alain.Chariot@ulg.ac.be Pierre.Close@ulg.ac.be.|GIGA-Molecular Biology of Diseases, University of Liège, 4000 Liège, Belgium.|GIGA-Research, University of Liège, 4000 Liège, Belgium.
Pierre
0000-0002-8844-9616
P
Close
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000235:genetics*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D014176:Protein Biosynthesis; D012343:RNA, Transfer / Q000378:metabolism*; D013891:Thiouridine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
C011701:5-carbomethoxymethyl-2-thiouridine; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D000067556:Internal Ribosome Entry Sites; D051821:Lymphoid Enhancer-Binding Factor 1; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D013891:Thiouridine; D012343:RNA, Transfer; C538729:ELP3 protein, human; D051548:Histone Acetyltransferases