Translation from unconventional 5′ start sites drives tumour initiation
Author: ["Ataman Sendoel","Joshua G. Dunn","Edwin H. Rodriguez","Shruti Naik","Nicholas C. Gomez","Brian Hurwitz","John Levorse","Brian D. Dill","Daniel Schramek","Henrik Molina","Jonathan S. Weissman","Elaine Fuchs"]
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Abstract
We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5′ untranslated regions in cancer, and expose new targets for therapeutic intervention. The translation of upstream open reading frames in skin tumour models protects some cancer-related mRNAs from global reductions in protein synthesis during the early stages of tumour initiation, suggesting that unconventional translation has a crucial role in tumorigenesis. Elaine Fuchs and colleagues uncover a role for the translation of upstream open reading frames (uORFs)—gene-expression regulatory elements present in many messenger RNAs—in skin tumour models. This oncogene-driven shift in translation shields some pro-tumorigenic mRNAs from global reductions in protein synthesis during the early stages of tumorigenesis, suggesting that tumour drivers may use uORF translation to enact oncogenic transformation.
Cite this article
Sendoel, A., Dunn, J., Rodriguez, E. et al. Translation from unconventional 5′ start sites drives tumour initiation. Nature 541, 494–499 (2017). https://doi.org/10.1038/nature21036
