Nijmegen breakage syndrome protein 1 (NBS1) modulates hypoxia inducible factor-1α (HIF-1α) stability and promotes in vitro migration and invasion under ionizing radiation

Hypoxia-inducible factor (HIF) is a heterodimer transcription factor complex that monitors the cellular response to the oxygen levels in cells. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-RAD5O-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-1 alpha stabilization is regulated by NBS1 and thereby promotes tumor cell migration/invasion. Here, we show that both NBS1 and HIF-1 alpha expression are up-regulated after exposure to IR, and NBS1 increases HIF-1 alpha 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-1 alpha and reduces the ubiquitination of HIF-1 alpha. Co-expression of HIF-1 alpha 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-1 alpha under IR, which leads to enhanced cancer cell migration and invasion. (C) 2015 Elsevier Ltd. All rights reserved.