HDAC and MAPK/ERK Inhibitors Cooperate To Reduce Viability and Stemness in Medulloblastoma

AbstractMedulloblastoma (MB), which originates from embryonic neural stem cells (NSCs) or neural precursors in the developing cerebellum, is the most common malignant brain tumor of childhood. Recurrent and metastatic disease is the principal cause of death and may be related to resistance within cancer stem cells (CSCs). Chromatin state is involved in maintaining signaling pathways related to stemness, and inhibition of histone deacetylase enzymes (HDAC) has emerged as an experimental therapeutic strategy to target this cell population. Here, we observed antitumor actions and changes in stemness induced by HDAC inhibition in MB. Analyses of tumor samples from patients with MB showed that the stemness markersBMI1 andCD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression ofBMI1 andCD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated withCD133 orBMI1 expression showed mitogen-activated protein kinase (MAPK)/ERK signaling as the most enriched processes in MB tumors. MAPK/ERK inhibition reduced expression of the stemness markers, hindered MB neurosphere formation, and its antiproliferative effect was enhanced by combination with NaB. These results suggest that combining HDAC and MAPK/ERK inhibitors may be a novel and more effective approach in reducing MB proliferation when compared to single-drug treatments, through modulation of the stemness phenotype of MB cells.
Source: Journal of Molecular Neuroscience - Category: Neuroscience Source Type: research