Elongator: mcm5s2 modification fosters breast cancer metastasis

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.