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.

Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche

“…In addition, the colony-forming efficiency of quiescent bulge HFSCs is poor, suggesting that they experience stress prior to coping with it (Blanpain et al, 2004). Finally, it is notable that stress-experiencing epidermal stem cells in vivo or in vitro activate an alternative translation route that their normal stem cell counterparts do not (Sendoel et al, 2017). While this ultimately enables them to produce higher levels of stress-coping factors, the stressed cells repress global protein synthesis, a feature that could make them less adept at wound repair (Sendoel et al, 2017).…”

“…Finally, it is notable that stress-experiencing epidermal stem cells in vivo or in vitro activate an alternative translation route that their normal stem cell counterparts do not (Sendoel et al, 2017). While this ultimately enables them to produce higher levels of stress-coping factors, the stressed cells repress global protein synthesis, a feature that could make them less adept at wound repair (Sendoel et al, 2017). In the future, it will be interesting to interrogate the extent to which these features eventually confer long-term cultured HFSCs an advantage over in vivo bulge HFSCs in rapid tissue regeneration in response to injury.…”

TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma

“…Indeed, Nrf2 signaling can be induced by many mechanisms (Ma, 2013), including activating Nrf2 and inactivating Keap1 mutations (Cancer Genome Atlas Network, 2015), oncogenic Ras (DeNicola et al, 2011), and ectopically expressed Sox2 in normal keratinocytes (Sendoel et al, 2017). Furthermore, identification of a SCC specific super enhancer driving Nrf2 transcription in Hras G12V initiated, Tgfbr2 -deficient SCCs suggest TGFβ independent mechanisms (Yang et al, 2015).…”

The eIF2-alpha kinase HRI: a potential target beyond the red blood cell

“…The upregulation of ATF4 via eIF2α phosphorylation may itself serve to attenuate mTOR activity through the induction of mTOR repressors including Sestrin2 and REDD1 [66–68]. In addition, phosphorylation of eIF2α may promote alternative translational mechanisms, such as those utilizing eIF2A [69] (Figure 3). …”