Abstract
Investigation of the mechanisms responsible for aggressive neuroblastoma and its poor prognosis is critical to identify novel therapeutic targets and improve survival. Enhancer of Zeste Homolog 2 (EZH2) is known to play a key role in supporting the malignant phenotype in several cancer types and knockdown of EZH2 has been shown to decrease tumorigenesis in neuroblastoma cells. We hypothesized that the EZH2 inhibitor, GSK343, would affect cell proliferation and viability in human neuroblastoma. We utilized four long-term passage neuroblastoma cell lines and two patient-derived xenolines (PDX) to investigate the effects of the EZH2 inhibitor, GSK343, on viability, motility, stemness and in vivo tumor growth. Immunoblotting confirmed target knockdown. Treatment with GSK343 led to significantly decreased neuroblastoma cell viability, migration and invasion, and stemness. GSK343 treatment of mice bearing SK-N-BE(2) neuroblastoma tumors resulted in a significant decrease in tumor growth compared to vehicle-treated animals. GSK343 decreased viability, and motility in long-term passage neuroblastoma cell lines and decreased stemness in neuroblastoma PDX cells. These data demonstrate that further investigation into the mechanisms responsible for the anti-tumor effects seen with EZH2 inhibitors in neuroblastoma cells is warranted.
Highlights
Neuroblastoma, a neural crest tumor, continues to be responsible for over 15% of all pediatric cancer deaths [1]
Immunoblotting revealed that Enhancer of Zeste Homolog 2 (EZH2) and H3K27me3 were both present in both the long-term passage neuroblastoma cell lines (Fig 1A) and the human neuroblastoma patient-derived xenolines (PDX) cells (Fig 1B and 1C)
Xiong and colleagues found that GSK343 decreased expression of cMyc in osteosarcoma cells [31], leading them to postulate that the effects of GSK343 on c-Myc were responsible for the decreased expression of EZH2 seen with GSK343 treatment [31]
Summary
Neuroblastoma, a neural crest tumor, continues to be responsible for over 15% of all pediatric cancer deaths [1]. Children with high-risk disease fare the most poorly, and minimal advances have been made in improving their outcomes [2]. Novel pathways and targets must be investigated to provide innovative therapeutic interventions for these children.
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