INT6/eIF3e represses E‐cadherin expression through HIF2α in lung carcinoma A549 cells.

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. [ABSTRACT FROM AUTHOR]