beta-arrestin 2 stimulates degradation of HIF-1 alpha and modulates tumor progression of glioblastoma

The basic function of beta-arrestin 2 (Arrb2) is to negatively regulate the G-protein-coupled receptor signaling pathway through facilitating receptor desensitization and internalization. Arrb2 has also been reported to play various roles in cancer pathology including the proliferation, migration, invasion, metastasis, and apoptosis of solid tumors. However, the molecular mechanisms underlying the tumorigenic capacities of Arrb2 have not been elucidated. Here, we show a novel function of Arrb2: Arrb2 facilitates the degradation of HIF-1 alpha, which is a master regulator of oxygen homeostasis. We also demonstrate that Arrb2 interacts with HIF-1 alpha and stimulates ubiquitin-mediated 26S proteasomal degradation of HIF-1 alpha by recruiting PHD2 and pVHL. Overexpression of Arrb2 in human glioblastoma cells suppresses HIF-1 alpha signaling, tumor growth, and angiogenesis. Consistent with this antitumorigenic effect of Arrb2, low Arrb2 expression levels correlate with high HIF-1 alpha expression and poor glioblastoma patient survival. These results collectively reveal a novel function of Arrb2 in the oxygen-sensing mechanism that directly regulates HIF-1 alpha stability in human cancers and suggest Arrb2 as a new potential therapeutic target for glioblastoma.