Mammalian eukaryotic translation initiation factor 3 (eIF3) is the largest complex of the translation initiation factors. The eIF3 complex is comprised of thirteen subunits, which are named eIF3a to eIF3 m in most multicellular organisms. The eIF3e gene locus is one of the most frequent integration sites of mouse mammary tumor virus (MMTV), which induces mammary tumors in mice. MMTV‐integration events result in the expression of C‐terminal‐truncated eIF3e proteins, leading to mammary tumor formation. We have shown that tumor formation can be partly caused by activation of hypoxia‐inducible factor 2α. To investigate the function of eIF3e in mammals, we generated eIF3e‐deficient mice. These eIF3e −/− mice are embryonically lethal, while eIF3e +/− mice are much smaller than wild‐type mice. In addition, eIF3e +/− mouse embryonic fibroblasts (MEFs) contained reduced levels of eIF3a and eIF3c subunits and exhibited reduced cellular proliferation. These results suggest that eIF3e is essential for embryonic development in mice and plays a role in maintaining eIF3 integrity.

Hypoxia‐inducible factor 2 α (HIF2α), a transcription factor playing a vital role in hypoxia, promotes cancer metastasis. We had previously reported that the cancer‐related gene integration site 6/eukaryotic translation initiation factor 3 subunit e (INT6/eIF3e) negatively regulates the protein stability of HIF2α in an oxygen‐independent manner. Presently, the downstream targets for INT6/eIF3e‐regulated HIF2α are unknown. Given the roles of HIF2α and INT6/eIF3e in epithelial–mesenchymal transition (EMT) that promotes cancer metastasis, we hypothesized that INT6/eIF3e‐regulated HIF2α controls EMT. This study shows that INT6/eIF3e knockdown in lung carcinoma A549 cells led to increased expression of HIF2α protein and an EMT‐like phenotypic change. The increased HIF2α subsequently repressed the E‐cadherin gene. Mechanistically, HIF2α interacts with the twist family bHLH transcription factor 1 (TWIST1) known to regulate EMT process, and binds to the proximal promoter region of E‐cadherin, repressing it. Collectively, our work demonstrates that HIF2α, regulated by INT6/eIF3e, represses the E‐cadherin gene through TWIST1 to enhance EMT, suggesting a role of the INT6/eIF3e‐HIF2α axis in cancer metastasis.