HIF sustain a transcriptional regulatory circuit of EPAS1 expression in renal clear cell carcinoma

Initiation and sustainment of oncogenic signaling is a hallmark of cancer evolution and progression. In renal clear cell carcinoma, loss of von Hippel-Lindau protein causes stabilization of hypoxia-inducible transcription factors (HIF) evoking a pseudo-hypoxic response, perturbing epithelial homeostasis and leading to cancer development. Although genetic polymorphisms link the EPAS1 oncogene (coding for HIF-2α) to renal cancer and anti-HIF-2 compounds emerge as renal tumor therapies, little is known about transcriptional dysregulation of this factor in renal malignancies. We use genetic, epigenetic and transcriptomic data from large patient cohorts and cell models to dissect mechanisms of augmented EPAS1 transcription in clear cell renal cell carcinoma. We define an oncogenic enhancer of EPAS1 which operates depending on the presence of HIF and renal lineage-specific factors, thereby providing evidence for an auto-regulatory feed-forward circuit of HIF-2α regulation which promotes renal cancer growth.