Nuclear-translocated endostatin downregulates hypoxia inducible factor-1α activation through interfering with Zn(II) homeostasis

Hypoxia-inducible factor-1α (HIF-1α) is key in tumor progression and aggressiveness as it regulates a series of genes involved in angiogenesis and anaerobic metabolism. Previous studies have shown that the transcriptional levels of HIF-1α may be downregulated by endostatin. However, the molecular mechanism by which endostatin represses HIF-1α expression remains unknown. The current study investigated the mechanism by which nuclear-translocated endostatin suppresses HIF-1α activation by disrupting Zn(II) homeostasis. Endostatin was observed to downregulate HIF-1α expression at mRNA and protein levels. Blockage of endostatin nuclear translocation by RNA interference of importin α1/β1 or ectopic expression of NLS-deficient mutant nucleolin in human umbilical vein endothelial cells co-transfected with small interfering (si)-nucleolin siRNA compromises endostatin-reduced HIF-1α expression. Nuclear-translocated apo-endostatin, but not holo-endostatin, significantly disrupts the interaction between CBP/p300 and HIF-1α by disturbing Zn(II) homeostasis, which leads to the transcriptional inactivation of HIF-1α. The results reveal mechanistic insights into the method by which nuclear-translocated endostatin downregulates HIF-1α activation and provides a novel way to investigate the function of endostatin in endothelial cells.