REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia

The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1 alpha expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1 alpha mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1 alpha gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1 alpha protein response and the suppression of HIF-1 alpha mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1 alpha promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1 alpha mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1 alpha-(but not HIF-2 alpha-) dependent manner. Finally, REST promotes the resolution of HIF-1 alpha protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1 alpha in prolonged hypoxia, thus contributing to the resolution of the HIF-1 alpha response.