EPAS1 and neoplasm: Through activation of the hypoxia-inducible transcription factors HIF-1α and HIF-2α, hypoxia regulates a plethora of downstream genes and promotes genomic instability, tumor tissue acidosis, angiogenesis, invasiveness, and tumor progression associated with increased metastatic behavior, which ultimately result in poor prognosis and resistance to apoptosis-mediated cancer therapies such as radio-chemotherapy, targeted therapy, and immunotherapy [231].