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

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Stress Response

Background:

• Hypoxia (low oxygen) promotes cancer cell plasticity and metastasis, primarily through transcriptional changes mediated by hypoxia-inducible factors (HIFs).
• Translational regulation during hypoxia, which precedes transcriptional effects, remains understudied.
• The role of translation initiation factors in hypoxia-induced cellular responses is largely unexplored.

Purpose of the Study:

• To investigate the role of translational control in acute hypoxic responses.
• To identify specific translation factors involved in hypoxia-induced cellular plasticity and metastasis.
• To explore therapeutic strategies targeting hypoxia-induced translational reprogramming.

Main Methods:

• Ribosome profiling to analyze global translation changes during acute hypoxia.
• Functional assays to assess the impact of eIF3d/eIF3e on hypoxic responses and cancer cell invasion.
• Analysis of eIF3e expression and copy number in breast cancer patient data.
• Small molecule screening to identify inhibitors of eIF3e-mediated translation.

Main Results:

• A selective translational response to acute hypoxia was identified, dependent on eukaryotic initiation factor 3 subunit d (eIF3d) and eIF3e.
• This eIF3d/eIF3e-dependent translation controls key hypoxic responses, including HIF1a accumulation and cellular invasion.
• Elevated eIF3e copy number and expression signatures correlate with poorer outcomes in breast cancer patients.
• Novel small molecules targeting eIF3e were found to reduce hypoxia and ER stress-induced translation.

Conclusions:

• The study uncovers critical roles for eIF3d/eIF3e in mediating cellular responses to hypoxia.
• Targeting eIF3e presents a potential strategy to inhibit stress-induced translation, plasticity, and metastasis in cancer.
• This work highlights translational control as a key mechanism in hypoxia-driven cancer progression.