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Published on: March 31, 2015
Inactivation of SMC2 shows a synergistic lethal response in MYCN-amplified neuroblastoma cells
Yuko Murakami-Tonami1, Satoshi Kishida1, Ichiro Takeuchi2
1Department of Molecular Biology; Nagoya University Graduate School of Medicine; Nagoya, Japan.
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.
Insights
MYCN amplifies the SMC2 gene in neuroblastoma, impacting DNA damage and cell death. Low SMC2 expression correlates with better survival in patients with MYCN-amplified tumors, suggesting SMC2 as a therapeutic target.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The condensin complex is crucial for mitosis but its interphase role is unknown.
- Neuroblastoma, a common childhood cancer, often has poor prognosis linked to MYCN gene amplification.
- The function of SMC2 (a condensin subunit) in neuroblastoma is not well understood.
Purpose of the Study:
- To investigate the role of SMC2 in MYCN-amplified neuroblastoma.
- To determine if MYCN regulates SMC2 expression.
- To explore SMC2 as a potential therapeutic target in neuroblastoma.
Main Methods:
- Transcriptional analysis of SMC2 in neuroblastoma cells.
- Investigating the regulatory relationship between MYCN and SMC2.
- Assessing the impact of SMC2 downregulation on DNA damage and apoptosis.
- Correlating SMC2 expression with patient survival data.
Main Results:
- MYCN directly regulates the transcription of the SMC2 gene.
- SMC2 cooperates with MYCN to regulate DNA damage response genes.
- SMC2 downregulation induces DNA damage and apoptosis in MYCN-amplified neuroblastoma cells.
- Low SMC2 expression is associated with improved survival in patients with MYCN-amplified neuroblastoma.
Conclusions:
- SMC2 plays a novel role in DNA damage response in neuroblastoma.
- SMC2 is a downstream target of MYCN in neuroblastoma.
- SMC2 represents a potential therapeutic target for MYCN-amplified neuroblastoma.
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