title: Nuclear-translocated endostatin downregulates hypoxia inducible factor-1α activation through interfering with Zn(II) homeostasis.
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.
authors.affiliation: School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Guo
authors.affiliation: National Engineering Laboratory for Anti‑Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: National Engineering Laboratory for Anti‑Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: National Engineering Laboratory for Anti‑Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Qi
authors.affiliation: National Engineering Laboratory for Anti‑Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Guanghua
authors.initials: G
authors.lastname: Liu
authors.affiliation: National Engineering Laboratory for Anti‑Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: National Institutes for Food and Drug Control, Beijing 100050, P.R. China.
authors.forename: Chunming
authors.initials: C
authors.lastname: Rao
authors.affiliation: National Institutes for Food and Drug Control, Beijing 100050, P.R. China.
authors.forename: Junzhi
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for Anti‑Tumor Protein Therapeutics, School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Yongzhang
authors.initials: Y
authors.lastname: Luo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D043169:Endostatins / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D014176:Protein Biosynthesis; D015032:Zinc / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050880:p300-CBP Transcription Factors; D015032:Zinc