Reprogramming of neuroblastoma cells by the histone deacetylase inhibitor valproic acid

Spontaneous and therapy-induced differentiation is one of the biological hallmarks of childhood neuroblastomas. The degree of differentiation towards ganglionic cells is recognized as the principal morphological feature to be of prognostic importance. We hypothesized that neuroblastoma cells contain a differentiation program, which can be activated either pharmacologically or by unknown endogenous mechanisms.

The histone deacetylase (HDAC) inhibitor valproic acid (VPA) induces morphological features of ganglionic differentiation in 4 neuroblastoma cell lines and inhibited HDACs in all cell lines studied. Using cDNA-microarrays, we found that VPA causes a shift of the transcriptome prior to morphological differentiation on correspondence analysis. Significant up-regulated genes belong to gene ontology annotations associated with neurogenesis/differentiation, cell adhesion and immune function. Comparison of these in-vitro experiments with patient samples from neuroblastomas with favorable histology (ganglioneuroblastoma) versus unfavorable histology (poorly differentiated neuroblastoma) revealed striking similarities in gene expression profiles.

In conclusion, our data suggest that the HDAC-inhibitor valproic acid is able to activate a differentiation program in neuroblastoma cells that converts the malignant phenotype towards a benign condition.