Translation from unconventional 5′ start sites drives tumour initiation

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.