Translation from Alternate Start Sites Enriches Oncogenic Proteins

Translational regulation is essential for determining protein abundance, and oncogenic drivers can alter the activity of eukaryotic initiation factors (eIF) and ribosomal proteins. To test the hypothesis that oncogenes modify protein synthesis programs to promote tumor initiation and progression, Sendoel and colleagues used a mouse model of premalignant induction of the transcription factor SOX2, a driver of squamous cell carcinoma (SCC), in the embryonic epidermis. Parallel RNA sequencing and ribosome profiling allowed a genome-wide comparison of transcription and translation, and 573 genes were identified that exhibited translational, but not transcriptional, differences in response to SOX2 expression. SOX2⁺ cells had a reduced translational efficiency compared with wild-type cells, which was generally was associated with reduced protein synthesis. However, a small subset of mRNAs, many of which were associated with cancer, was efficiently translated in SOX2⁺ cells, suggesting that cancer-related genes may escape translational suppression. SOX2 expression increased ribosome occupancy at 5′ untranslated regions and the use of upstream open reading frames (uORF), many of which contained alternative CUG codons instead of the conventional AUG initiation site, suggesting that translation from uORFs increases the translation efficiency of cancer-related mRNAs. Depletion of translational regulators in an in vivo RNAi screen revealed that normal cells, but not cancer cells, depended on the conventional eIF2α (encoded by EIF2S1) for translation and cell growth. In contrast, the alternative initiation factor eIF2A was required for SCC tumor initiation and translation from CUG uORF start codons. Further, data from The Cancer Genome Atlas showed that the EIF2A locus is frequently amplified in patients with SCC, and increased EIF2A mRNA expression is associated with reduced overall survival. In addition to suggesting a mechanism by which cancer-related mRNAs may be translated from uORFs during global translational repression, these findings suggest the potential for therapeutic targeting of eIF2A-mediated translation.

Sendoel A, Dunn JG, Rodriguez EH, Naik S, Gomez NC, Hurwitz B, et al. Translation from unconventional 5′ start sites drives tumour initiation. Nature 2017;541:494–9.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.