title: Inactivation of SMC2 shows a synergistic lethal response in MYCN-amplified neuroblastoma cells.
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.
authors.affiliation: Department of Molecular Biology; Nagoya University Graduate School of Medicine; Nagoya, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Murakami-Tonami
authors.affiliation: Department of Molecular Biology; Nagoya University Graduate School of Medicine; Nagoya, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kishida
authors.affiliation: Department of Computer Science/Scientific and Engineering Simulation; Nagoya Institute of Technology; Nagoya, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takeuchi
authors.affiliation: Laboratory of Genome Structure & Function; Institute of Molecular and Cellular Biosciences; The University of Tokyo; Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katou
authors.affiliation: Department of Pediatrics and Center for Childhood Cancer Research; Children's Hospital of Philadelphia; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: Division of Genetics; National Cancer Institute; Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Division of Molecular Oncology; Aichi Cancer Center Research Institute; Nagoya, Japan; Division of Epigenomics; Aichi Cancer Center Research Institute; Nagoya, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Division of Molecular Oncology; Aichi Cancer Center Research Institute; Nagoya, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.affiliation: Laboratory of Genome Structure & Function; Institute of Molecular and Cellular Biosciences; The University of Tokyo; Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.affiliation: Department of Biological Science; Faculty of Science and Engineering; Chuo University; Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Department of Molecular Biology; Nagoya University Graduate School of Medicine; Nagoya, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C459801:MYCN protein, human; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C490381:SMC2 protein, human; C550185:SMC2 protein, mouse; D000251:Adenosine Triphosphatases; C580922:SMC4 protein, human
keywords: DNA damage response; MYCN; condensin complex; neuroblastoma; synergistic lethal response