Inactivation of SMC2 shows a synergistic lethal response in MYCN-amplified neuroblastoma cells

Cell Cycle. 2014;13(7):1115-31. doi: 10.4161/cc.27983. Epub 2014 Feb 7.

Abstract

The condensin complex is required for chromosome condensation during mitosis; however, the role of this complex during interphase is unclear. Neuroblastoma is the most common extracranial solid tumor of childhood, and it is often lethal. In human neuroblastoma, MYCN gene amplification is correlated with poor prognosis. This study demonstrates that the gene encoding the condensin complex subunit SMC2 is transcriptionally regulated by MYCN. SMC2 also transcriptionally regulates DNA damage response genes in cooperation with MYCN. Downregulation of SMC2 induced DNA damage and showed a synergistic lethal response in MYCN-amplified/overexpression cells, leading to apoptosis in human neuroblastoma cells. Finally, this study found that patients bearing MYCN-amplified tumors showed improved survival when SMC2 expression was low. These results identify novel functions of SMC2 in DNA damage response, and we propose that SMC2 (or the condensin complex) is a novel molecular target for the treatment of MYCN-amplified neuroblastoma.

Keywords: DNA damage response; MYCN; condensin complex; neuroblastoma; synergistic lethal response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Animals
  • Apoptosis / genetics
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Damage / genetics
  • Genome-Wide Association Study
  • HEK293 Cells
  • Humans
  • Mice
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism

Substances

  • Carrier Proteins
  • Chromosomal Proteins, Non-Histone
  • MYCN protein, human
  • MYCN protein, mouse
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • SMC2 protein, human
  • SMC2 protein, mouse
  • Adenosine Triphosphatases
  • SMC4 protein, human