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Gene expression profiling in response to the histone deacetylase inhibitor BL1521 in neuroblastoma
Annemieke J M de Ruijter1, Rutger J Meinsma, Peter Bosma
1Academic Medical Centre, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Department of Pediatrics/Emma Children's Hospital and Clinical Chemistry, PO Box 22700, 1100 DE Amsterdam, The Netherlands.
Abstract:
Neuroblastoma is a childhood tumor with a poor survival in advanced stage disease despite intensive chemotherapeutic regimes. The new histone deacetylase (HDAC) inhibitor BL1521 has shown promising results in neuroblastoma. Inhibition of HDAC resulted in a decrease in proliferation and metabolic activity, induction of apoptosis and differentiation of neuroblastoma cells. In order to elucidate the mechanism mediating the effects of BL1521 on neuroblastoma cells, we investigated the gene expression profile of an MYCN single copy (SKNAS) and an MYCN amplified (IMR32) neuroblastoma cell line after treatment with BL1521 using the Affymetrix oligonucleotide array U133A. An altered expression of 255 genes was observed in both neuroblastoma cell lines. The majority of these genes were involved in gene expression, cellular metabolism, and cell signaling. We observed changes in the expression of vital genes belonging to the cell cycle (cyclin D1 and CDK4) and apoptosis (BNIP3, BID, and BCL2) pathway in response to BL1521. The expression of 37 genes was altered by both BL1521 and Trichostatin A, which could indicate a common gene set regulated by different HDAC inhibitors. BL1521 treatment changed the expression of a number of MYCN-associated genes. Several genes in the Wnt and the Delta/Notch pathways were changed in response to BL1521 treatment, suggesting that BL1521 is able to induce the differentiation of neuroblastoma cells into a more mature phenotype.
Insights
The novel histone deacetylase (HDAC) inhibitor BL1521 shows promise for neuroblastoma treatment by altering gene expression, inducing apoptosis, and promoting differentiation. This HDAC inhibitor offers a potential new therapeutic avenue for this aggressive childhood cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroblastoma is a prevalent childhood cancer with poor outcomes in advanced stages, necessitating novel therapeutic strategies.
- Histone deacetylase (HDAC) inhibitors represent a promising class of drugs, with BL1521 demonstrating potential efficacy in preclinical neuroblastoma models.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the effects of the novel HDAC inhibitor BL1521 on neuroblastoma cells.
- To investigate the gene expression profile changes induced by BL1521 in both MYCN single copy and MYCN amplified neuroblastoma cell lines.
Main Methods:
- Treatment of SKNAS (MYCN single copy) and IMR32 (MYCN amplified) neuroblastoma cell lines with BL1521.
- Gene expression profiling using the Affymetrix oligonucleotide array U133A.
- Analysis of gene expression changes in response to BL1521 and comparison with Trichostatin A (TSA) treated cells.
Main Results:
- BL1521 treatment altered the expression of 255 genes in both neuroblastoma cell lines, primarily involved in gene expression, metabolism, and signaling.
- Significant changes were observed in cell cycle (e.g., cyclin D1, CDK4) and apoptosis (e.g., BNIP3, BID, BCL2) pathway genes.
- BL1521 modulated MYCN-associated genes and pathways like Wnt and Delta/Notch, suggesting induction of cellular differentiation.
Conclusions:
- BL1521 effectively alters gene expression in neuroblastoma cells, impacting key pathways involved in cell cycle, apoptosis, and differentiation.
- The observed changes suggest that BL1521 promotes neuroblastoma cell differentiation into a more mature phenotype.
- BL1521 represents a potential therapeutic agent for neuroblastoma, warranting further clinical investigation.
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