Hypoxia-inducible factor independent down-regulation of thioredoxin-interacting protein in hypoxia

Thioredoxin-Interacting Protein (Txnip) is an important regulator of glucose metabolism and functions by inhibiting cellular glucose uptake. The expression of the Txnip gene is sensitive to glucose availability and is negatively correlated with the glycolytic rate. Here we show that hypoxia induces a rapid decrease in Txnip mRNA and protein expression in a Hypoxia-Inducible Factor independent manner. Hypoxia caused reduced binding of the glucose responsive MondoA:Mlx transcription factor to the carbohydrate response elements (ChoREs) in the Txnip promoter. Our data suggest that hypoxia decreases MondoA:Mlx activity by increasing glycolytic flux, leading to the depletion of glycolytic intermediates which normally activate MondoA:Mlx. Hypoxia dependent Txnip down-regulation may be an important compensatory mechanism through which cancer cells adapt their metabolism to low oxygen concentrations.