eIF3d and eIF3e mediate selective translational control of hypoxia that can be inhibited by small molecules

Exposure to hypoxia is linked to increased cellular plasticity and enhanced metastasis, effects that are primarily attributed to the transcriptional activation of large gene programs downstream of hypoxia-inducible factors (HIFs). However, translational effects in hypoxia, which likely precede transcriptional effects, have remained largely unexplored. Using ribosome profiling, we uncovered a selective translational response in acute hypoxia that is eukaryotic initiation factor (eIF)3d/eIF3e dependent and controls downstream hypoxic responses, including HIF1α accumulation and cellular invasion. We further demonstrated that eIF3e copy number and eIF3e and eIF3d expression signatures are associated with worsened outcomes for patients with breast cancer. Finally, we identified a class of novel small molecules that target eIF3e specifically, reducing the translational response to hypoxia and to endoplasmic reticulum (ER) stress, another stressor that is dependent on eIF3d-/eIF3e-mediated translation. Our data uncover critical functions for eIF3d/eIF3e in the hypoxic response and identify a potential means to inhibit stress-induced translation, and potentially plasticity and metastasis, mediated by eIF3e.