Elp 3 links tRNA modification to IRES-dependent translation of LEF 1 to sustain metastasis in breast cancer

The Rockefeller University Press $30.00 J. Exp. Med. 2016 Vol. 213 No. 11 2503–2523 https://doi.org/10.1084/jem.20160397 2503 INT ROD UCT ION Cancer metastases at distant organs require tumor cell adaption. Common adaptive responses include modifications in the tumor microenvironment, as well as changes in the proteome of the tumor itself to sustain cell invasion, survival, and establishment of a distal secondary tumor (Taddei et al., 2013; Oskarsson et al., 2014). Several signaling pathways are aberrantly activated in metastatic cancer cells. Among them, the WNT and TGFβ pathways are prominent in promoting metastasis (Massagué, 2008; Anastas and Moon, 2013). Indeed, the WNT–TCF pathway is essential for dissemination and relapse of metastatic lung adenocarcinoma (Nguyen et al., 2009) and in supporting breast cancer metastatic colonization (Malanchi, 2012; Jang et al., 2015). Downstream of WNT activation, the transcription factor LEF1 was further pointed out as a crucial effector to support formation of WNT-dependent metastases (Nguyen et al., 2009). LEF1 expression is also induced by other signals, including TGFβ and mediates breast tumor cells invasion (Nawshad and Hay, 2003; LaGamba et al., 2005; Nguyen et al., 2005; Medici et al., 2006). The expression of LEF1 protein is also regulated posttranscriptionally, through the presence of a regulatory internal ribosome entry site (IRES) sequence in its 5′ untranslated region (UTR; Jimenez et al., 2005). Indeed, the oncogenic LEF1 protein is predominantly produced by a cap-independent translational mechanism that requires the recruitment of several proteins to its IRES sequence, namely canonical translation initiation factors and IRES trans-acting factors (ITAFs; Jimenez et al., 2005; Tsai et al., 2011, 2014). However, the biological consequences of IRES-dependent regulation of LEF1 expression in the context of breast cancer remain poorly explored. Translational control of protein expression is now recognized as a crucial component of human cancer development and progression (Silvera et al., 2010). mRNA translation requires the pairing between codons in the 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 ELP3and 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. Elp3 links tRNA modification to IRES-dependent translation of LEF1 to sustain metastasis in breast cancer