Aquatic mammals, such as cetaceans experience various depths, with accordingly diverse oxygenation, thus, cetaceans have developed adaptations for hypoxia, but mechanisms underlying this tolerance to low oxygen are unclear. Here we analyzed VHL and HIF-2 alpha, in the hypoxia signaling pathway. Variations in VHL are greater than HIF-2 alpha between cetaceans and terrestrial mammals, and beluga whale VHL (BW-VHL) promotes HIF-2 alpha degradation under hypoxia. BW-VHL catalyzes BW-HIF-2 alpha to form K48-linked polyubiquitin chains mainly at the lysine 429 of BW-HIF-2 alpha (K429) and induces BW-HIF-2 alpha for proteasomal degradation. W100 within BW-VHL is a key site for BW-VHL functionally and BW-VHL enhances transcriptional activity of BW-HIF-2 alpha under hypoxia. Our data therefore reveal that BW-VHL has a unique function that may contribute to hypoxic adaptation.