Downregulation of AIF by HIF-1 contributes to hypoxia-induced epithelial–mesenchymal transition of colon cancer

Recently, we have reported that apoptosis-inducing factor (AIF) regulates the epithelial-mesenchymal transition (EMT) process of cancers, but the mechanisms underlying the regulation of AIF expression in cancers remain greatly unknown. Here, we report that hypoxia inversely correlates with the expression of AIF in tumor tissues from a cohort of colon cancer patients and inhibits AIF expression in multiple colon cancer cell lines. This inhibition is mediated by hypoxia-inducible factor-1 (HIF-1), which transcriptionally represses AIF through direct binding to the hypoxia-response element in AIF promoter as revealed by luciferase reporter and chromatin immunoprecipitation assays. We also show that downregulation of AIF contributes to hypoxia-induced EMT as overexpression or silencing of AIF partially reverses or potentiates the EMT program initiated by hypoxic treatment. Mechanistic study reveals that downregulation of AIF by hypoxia causes oxidative inactivation of the lipid phosphatase activity of phosphatase and tensin homolog on chromosome 10 (PTEN), with ensuing activation of Akt kinase, phosphorylation of the Akt substrate GSK-3β and activation of WNT/β-catenin signaling in colon cancer cells. These results identify AIF as a novel target gene of HIF-1 and reveal the role of AIF downregulation in hypoxia-induced EMT.