Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.
Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer.
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ELP3将TRNA修饰与IRES依赖性LEF1的翻译联系起来，以维持乳腺癌的转移。
DOI：
10.1084/jem.20160397
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发表时间：
2016-10-17
期刊：
影响因子：
--
通讯作者：
Close P
中科院分区：
文献类型：
--
作者：
Delaunay S;Rapino F;Tharun L;Zhou Z;Heukamp L;Termathe M;Shostak K;Klevernic I;Florin A;Desmecht H;Desmet CJ;Nguyen L;Leidel SA;Willis AE;Büttner R;Chariot A;Close P
Delaunay et al. reveal the role of U34 tRNA-modifying enzymes in the regulation of specific mRNA translation to support cell invasion and metastasis. 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.
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