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

Abstract

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.

Hypoxia downregulates protein S expression

“…Although HIF1 is a well-documented, general transcriptional activator, it has also been identified as a transcriptional repressor. For example, HIF1 interacts with genes such as AIF, 22 cyclin D1, 23 and Bid 24 and reduces their transcription under hypoxia. In addition, HIF1a regulates transcription of a variety of microRNAs that, in turn, regulate expression of various target mRNAs 25 ; in these cases, HIF1 can be said to be an indirect transcriptional regulator of these mRNAs.…”

Proteome dynamics analysis identifies functional roles of SDE2 and hypoxia in DNA damage response in prostate cancer cells

“…In this study, we identified and validated that SDE2, a recently characterized protein that is involved in the DNA damage response pathway, is downregulated by hypoxia. Interestingly, unlike many proteins downregulated under hypoxia due to HIF1α-mediated transcriptional repression, such as apoptosis-inducing factor and antigen-presenting MHC class I molecules ( 50 , 51 ), the degradation of SDE2 under hypoxia is independent of both HIF1α and HIF2α, and in some cases, the mRNA level of SDE2 was even increased upon hypoxia treatment, suggesting the involvement of critical posttranslational regulation pathways. We were able to confirm that hypoxia degrades SDE2 through the increase of its ubiquitination level and promotes proteasome-dependent protein turnover.…”

Targeting PTEN in Colorectal Cancers

“…Binding of thioredoxin-1 to PTEN Cys212 of the C2 domain of PTEN inhibits PTEN membrane translocation and activation (Meuillet et al 2004). Hypoxia, a hallmark of tumours, promotes transcriptional inhibition of AIF (tumour apoptosis-inducing factor) through HIF-1 (hypoxia induced factor-1), resulting in oxidative inactivation of PTEN and epithelial-mesenchymal transition of colorectal cancer (Xiong et al 2016). Oxidation of PTEN-binding partners can also affect PTEN activity.…”