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

Int J Biochem Cell Biol. 2015 Jul;64:229-38. doi: 10.1016/j.biocel.2015.04.015. Epub 2015 May 7.

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.

Keywords: HIF-1α; Ionizing radiation; Migration/invasion; NBS1; Ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Cell Cycle Proteins / physiology*
  • Cell Movement / radiation effects*
  • Epithelial-Mesenchymal Transition
  • Gene Expression
  • HEK293 Cells
  • Half-Life
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • MCF-7 Cells
  • Neoplasm Invasiveness
  • Nuclear Proteins / physiology*
  • Prognosis
  • Protein Stability
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NBN protein, human
  • Nuclear Proteins