von Hippel-Lindau-binding protein 1 (VBP1) physically interacts with pVHL, an E3-ubiquitin ligase, which degrades HIF-1α in an oxygen-dependent manner. HIF-1 is a key regulator of adaptive responses to a lack of oxygen that controls glucose metabolism, angiogenesis, proliferation, invasion, and metastasis. However, the role of VBP1 in pVHL-mediated degradation of HIF-1α is not yet known. In this study, we show that VBP1 enhances the stability of pVHL and facilitates pVHL-mediated ubiquitination of HIF-1α. Furthermore, VBP1 suppresses HIF-1α-induced epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. These findings suggest that VBP1 is a bona fide tumor suppressor protein associated with HIF-1α regulation.