2. Academic Validation
  3. eIF3d and eIF3e mediate selective translational control of hypoxia that can be inhibited by novel small molecules

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

  • bioRxiv. 2025 May 29:2025.05.29.656739. doi: 10.1101/2025.05.29.656739.
Stephen C Purdy 1 2,  Kate Matlin 1 3 4,  Christopher Alderman 3 4 5,  Amber Baldwin 3,  Natasha Shrivastava 1,  Somnath Dutta 6,  Kristofor J Webb 7,  Arthur Wolin 1 4,  Dillon P Boulton 1 8,  Jyoti Kapali 9,  John D Landua 9,  Michael T Lewis 9,  M Cecilia Caino 1 2 4 8,  James C Costello 1 2 8 5,  William Old 7 10,  Xiang Wang 1 6,  Rui Zhao 2 3 4 5,  Heide L Ford 1 2 4 8 5,  Neelanjan Mukherjee 3 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Colorado Anschutz Medical Campus (AMC), Aurora, CO, USA.
  • 2 Cancer Biology Program, University of Colorado Anschutz Medical Campus (AMC), Aurora, CO, USA.
  • 3 Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus (AMC), Aurora, CO, USA.
  • 4 Molecular Biology Program, University of Colorado Anschutz Medical Campus (AMC), Aurora, CO, USA.
  • 5 Medical Scientist Training Program, University of Colorado Anschutz Medical Campus (AMC), Aurora, CO, USA.
  • 6 Department of Chemistry, University of Colorado, Boulder, CO, USA.
  • 7 Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA.
  • 8 Pharmacology and Molecular Medicine Program, University of Colorado Anschutz Medical Campus (AMC), Aurora, CO, USA.
  • 9 Departments of Molecular and Cellular Biology and Radiology, Lester and Sue Smith Breast Center, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 10 Current address: Enveda 5700 Flatiron Parkway Boulder, CO 80301.
PMID: 40501575 DOI: 10.1101/2025.05.29.656739
Abstract

Exposure to hypoxia is linked to increased cellular plasticity and enhanced metastasis; effects which are primarily attributed to the transcriptional activation of large gene programs downstream of hypoxia inducible factors (HIFs). However, translational effects in hypoxia, that likely precede transcriptional effects, have remained largely unexplored. Using ribosome-profiling, we uncovered a selective translational response in acute hypoxia that is eIF3d/eIF3e-dependent and controls downstream hypoxic responses including HIF1a accumulation and cellular invasion. We further demonstrated that eIF3e copy number and an eIF3e-expression signature are associated with worsened outcomes for breast Cancer patients. Finally, we identified a class of novel small molecules that target eIF3e specifically, reducing the translational response to hypoxia and to 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.

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