Background: A growing and proliferating cell requires enhanced metabolic capacity for accumulation of biomass and replication of the genomic DNA. It is well documented that cancer cells alter their metabolism to meet the biosynthetic challenge of growth and proliferation. The metabolic pathways critical for driving neuroblastoma development are poorly understood.
Methods: We isolated and propagated a population of neuroblastoma stem-like cells from tumors developed in TH-MYCN mice, a well-characterized mouse model of human neuroblastoma. We performed microarray gene expression profiling of these tumor stem cells in comparison with their parental primary neuroblastoma cells and identified metabolic pathways that are activated in neuroblastoma stem cells. We further conducted loss- and gain-of-function studies to investigate the functional significance of these metabolic pathways in regulation of neuroblastoma stem cell activities and the molecular mechanisms for the activation these pathways in neuroblastoma stem cells.
Results: We found that neuroblastoma stem cells display significantly higher expression of genes coding for enzymes in the serine-glycine synthesis pathway, which generates biosynthetic precursors essential for the production of proteins, nucleic acids, fatty acids, and the membranes needed for cell proliferation. Transcriptional activation of the pathway genes are also observed in high-risk human neuroblastoma tumors and are significantly associated with poor prognosis in neuroblastoma patients. The serine-glycine synthesis pathway is required for the survival, proliferation, and tumorigenicity of mouse neuroblastoma stem cells and human neuroblastoma cell lines. Our investigation further revealed a key role of histone H3 lysine 9 methylation states in transcription control of the serine-glycine synthesis pathway.
Conclusions: Our findings identify an epigenetic program for transcriptional activation of cancer metabolism in neuroblastoma stem cells and suggest new therapeutic strategies for high-risk neuroblastoma.