Valproic acid induces polarization, neuronal-like differentiation of a subpopulation of C6 glioma cells and selectively regulates transgene expression

Glioblastoma is the most frequent primary brain tumor, and for which standard therapies have not significantly increased the survival of patients. Recently, chromatin alterations have been linked to the pathogenesis of cancer, and drugs that modify chromatin structure, such as inhibitors of histone deacetylases (iHDAC), are now considered as a valuable strategy for the treatment of cancer. For instance, valproic acid (VPA), an iHDAC originally used for the treatment of bipolar disorders and epilepsy, is now being used in cancer therapy. In this work we show that VPA induces morphological changes in murine astrocytoma C6 cells, which are associated with inhibition of cell proliferation, growth arrest, decreased cell migration, cell death and histone 4 hyperacetylation. VPA-treated cells extended processes with characteristics similar to the structure of a growth cone, and we also observed both a down-regulation of glial protein markers and increased expression of a neuronal specific protein after VPA treatment. Finally, there is an increase in the expression of a reporter transgene driven by a neuronal-specific promoter and a decrease of gene expression using a glial specific promoter in VPA-treated cells. These results indicate that VPA induces a specific differentiation of C6 cells toward a neuronal-like phenotype. The present data highlight the importance of epigenetic phenomena in the development and differentiation of the nervous system.