Distant metastasis is a major cause of death in patients with colorectal cancer (CRC), but the management of advanced and metastatic CRC still remains problematic due to the distinct molecular alterations during tumor progression. Tumor angiogenesis is a key step in tumor growth, invasion, and metastasis. However, the signaling pathways involved in angiogenesis are poorly understood. The results of the present study showed that secretogranin II (SCG2) was significantly downregulated in malignant CRC tissues and higher expression of SCG2 was correlated with longer disease-free survival and overall survival of CRC patients. The results of an animal study showed that ectopic expression of SCG2 significantly inhibited CRC tumor growth by disrupting angiogenesis. Furthermore, the inhibition of expression of vascular endothelial growth factor (VEGF) by SCG2 and rescue of VEGF efficiently blocked SCG2-induced inhibition of angiogenesis. Investigations into the underlying mechanism suggested that SCG2 promoted degradation of hypoxia-inducible factor (HIF)-1α by interacting with the von Hippel-Lindau (VHL) tumor suppressor in CRC cells. Blocking of degradation of HIF-1α efficiently attenuated the SCG2-mediated decrease in expression of VEGF in CRC cells. Collectively, these results demonstrated that treatment with SCG2 efficiently inhibited CRC tumor growth by disrupting the activities of HIF-1α/VEGF, thereby clarifying the anti-tumor and anti-angiogenesis roles of SCG2 in CRC, while providing a novel therapeutic target and a potential prognostic marker of disease progression.This article is protected by copyright. All rights reserved.