The Repressor Element‐1 Silencing Transcription Factor (REST) regulates the Hypoxia Inducible Factor (HIF) network through a novel negative feedback loop

Abstract

Hypoxia induces a number of metabolic changes with profound consequences for cell physiology and pathophysiology. Our understanding of the complex response to hypoxia has been focused on the Hypoxia‐Inducible Factor (HIF) and its regulation by prolyl‐hydroxylases (PHD). In solid tumours, both intra‐tumoral hypoxia and mutations in tumour suppressor genes can lead to the overexpression of HIF, a feature that has been associated with poor prognosis.The Repressor Element‐1 Silencing Transcription Factor (REST), is best characterized as a transcriptional repressor of neuronal genes in non‐neuronal tissues. More recently, REST was found to be affected by ischemia and to be down regulated in breast and colon cancer. This lead us to investigate if REST was an hypoxic sensitive transcription factor and if it interacts with the HIF pathway.Hypoxia induced an increase in REST translocation to the nucleus. siRNA knockdown of REST increased HIF, PHD2 and PHD3 protein expression. REST was found to be recruited to the HIF promoter, and HIF was recruited to the REST promoter in a hypoxia dependent way, indicating a novel negative feedback loop involving REST and HIF. In conclusion, REST was identified as a novel hypoxia‐sensitive transcriptional repressor that negatively regulates HIF, PHD2/3, acting as a novel negative feedback loop in the hypoxia response.