title: Nijmegen breakage syndrome protein 1 (NBS1) modulates hypoxia inducible factor-1α (HIF-1α) stability and promotes in vitro migration and invasion under ionizing radiation.
abstract: Hypoxia-inducible factor (HIF) is a heterodimer transcription factor complex that monitors the cellular response to the oxygen levels in cells. Hypoxia-inducible factor-1α (HIF-1α) has been shown to be stabilized by ionizing radiation (IR) and its stabilization promotes tumor progression and metastasis. Nijmegen breakage syndrome protein 1 (NBS1), a component of the MRE11-RAD50-NBS1 complex, plays an important role in the cellular response to DNA damage but its overexpression contributes to transformation and has been found to correlate with metastasis. However, whether NBS1 participates in IR-induced metastasis needs to be further determined. The aim of this study is to investigate whether radiation-induced HIF-1α stabilization is regulated by NBS1 and thereby promotes tumor cell migration/invasion. Here, we show that both NBS1 and HIF-1α expression are up-regulated after exposure to IR, and NBS1 increases HIF-1α expression at the protein level. In addition, IR treatment promotes the epithelial-mesenchymal transition (EMT) and in vitro cell migration and invasion activity, which could be abolished by suppression of NBS1. Furthermore, NBS1 directly interacts with HIF-1α and reduces the ubiquitination of HIF-1α⋅ Co-expression of HIF-1α and NBS1 in primary tumors of patients with lung adenocarcinoma correlates with a worse prognosis. These results provide a new function of NBS1 in stabilizing HIF-1α under IR, which leads to enhanced cancer cell migration and invasion.
authors.affiliation: Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Kuo
authors.affiliation: Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
authors.forename: Han-Tsang
authors.initials: HT
authors.lastname: Wu
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Division of Thoracic Surgery, Dept. of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Jung-Jyh
authors.initials: JJ
authors.lastname: Hung
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Dept of Pathology, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors.forename: Teh-Ying
authors.initials: TY
authors.lastname: Chou
authors.affiliation: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Teng
authors.affiliation: Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan; Research Center for Tumor Medical Science, Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan. Electronic address: wukj@mail.cmu.edu.tw.
authors.forename: Kou-Juey
authors.initials: KJ
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000502:physiology*; D002465:Cell Movement / Q000528:radiation effects*; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000502:physiology*; D011379:Prognosis; D055550:Protein Stability; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C112156:NBN protein, human; D009687:Nuclear Proteins
keywords: HIF-1α; Ionizing radiation; Migration/invasion; NBS1; Ubiquitination