Neuroblastoma cell growth and survival promoted by DNMT3B and its inhibition demonstrates anti-tumor effects
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Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics
Published on: January 11, 2019
Kazuya Izumi1,2, Hiromasa Aoki1, Kohki Toriuchi1
1Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Aichi, Japan.
Background:
Neuroblastoma is one of the most common childhood tumors. As tumor suppressor genes are frequently silenced via promoter hypermethylation in cancers, targeting DNA methylation has become a promising therapeutic approach. Despite the therapeutic potential of targeting DNA methylation in neuroblastoma, conventional inhibitors of DNA methyltransferases (DNMTs) reportedly exhibit inadequate therapeutic efficacy and intolerable toxicity. Therefore, a more selective approach targeting DNA methylation enzymes that contribute to neuroblastoma progression is warranted.
Methods:
DNMT3B expression in neuroblastoma patients was analyzed using public microarray data. The role of DNMT3B in neuroblastoma was assessed using neuroblastoma cell lines and a cell line-derived neuroblastoma xenograft model. Gene expression changes induced by DNMT3B knockdown in neuroblastoma cells were comprehensively analyzed using RNA sequencing.
Results:
DNMT3B expression was higher in advanced neuroblastoma patients and correlated with poor prognosis. DNMT3B knockdown induced DNA demethylation, leading to enhanced apoptosis-related gene expression and cellular functions. Tumor progression was weakened by DNMT3B knockdown both in vitro and in vivo. The DNMT3B inhibitor nanaomycin A showed anti-tumor effects in a neuroblastoma xenograft model.
Conclusion:
This study revealed the tumor-promoting role of DNMT3B in neuroblastoma through in vitro analyses and provided in vivo evidence that DNMT3B inhibition suppresses tumor growth.
Impact:
We propose selective inhibition of DNMT3B as a new approach in neuroblastoma treatment. DNMT3B enhanced disease progression in neuroblastoma cell lines and a cell line-derived xenograft model. Nanaomycin A, a small-molecule inhibitor of DNMT3B, exhibited significant anti-tumor effects on neuroblastoma in vivo, supporting the potential for targeting DNMT3B in neuroblastoma treatment.
Insights
Selective inhibition of DNA methyltransferase 3B (DNMT3B) shows promise for treating neuroblastoma. Targeting DNMT3B suppresses tumor growth and enhances apoptosis, offering a potential new therapeutic strategy for this childhood cancer.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Neuroblastoma is a common childhood cancer.
- DNA methylation is a key epigenetic mechanism in cancer development.
- Current DNA methyltransferase inhibitors have limited efficacy and high toxicity for neuroblastoma.
Purpose of the Study:
- To investigate the role of DNA methyltransferase 3B (DNMT3B) in neuroblastoma progression.
- To evaluate the therapeutic potential of selective DNMT3B inhibition in neuroblastoma.
Main Methods:
- Analyzed DNMT3B expression in neuroblastoma patient data.
- Assessed DNMT3B function in neuroblastoma cell lines and xenograft models.
- Utilized RNA sequencing to analyze gene expression changes after DNMT3B knockdown.
Main Results:
- Elevated DNMT3B expression correlates with advanced neuroblastoma and poor prognosis.
- DNMT3B knockdown induced DNA demethylation, increased apoptosis-related gene expression, and inhibited tumor growth in vitro and in vivo.
- The DNMT3B inhibitor nanaomycin A demonstrated anti-tumor effects in a neuroblastoma xenograft model.
Conclusions:
- DNMT3B plays a tumor-promoting role in neuroblastoma.
- Selective inhibition of DNMT3B is a potential therapeutic strategy for neuroblastoma.
- Nanaomycin A shows promise as a DNMT3B-targeted therapy for neuroblastoma.
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