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

Abstract

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.

Keywords: E-cadherin; EMT; HIF2α; INT6/eIF3e; TWIST1; cancer metastasis; gene regulation.