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

Guo,Lifang; Chen,Yang; He,Ting; Qi,Feifei; Liu,Guanghua; Fu,Yan; Rao,Chunming; Wang,Junzhi; Luo,Yongzhang

doi:10.3892/mmr.2015.3223

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

Authors:
- Lifang Guo
- Yang Chen
- Ting He
- Feifei Qi
- Guanghua Liu
- Yan Fu
- Chunming Rao
- Junzhi Wang
- Yongzhang Luo
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Affiliations: School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China, National Engineering Laboratory for Anti‑Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China, National Institutes for Food and Drug Control, Beijing 100050, P.R. China
Published online on: January 19, 2015 https://doi.org/10.3892/mmr.2015.3223
Pages: 3473-3480

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Abstract

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.

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