EPAS1 and neoplasm: Under normoxic conditions, HIF-1α can be downregulated through ubiquitination and von Hippel-Lindau protein-mediated proteasomal degradation, while stabilization of HIF-1α and/or HIF-2α under hypoxic stress leads to transcriptional upregulation of many hypoxia-responsive genes associated with the metabolism and immunity of tumor cells and immune cells (47).