PT  - JOURNAL ARTICLE
AU  - Mariane da Cunha Jaeger
AU  - Eduarda Chiesa Ghisleni
AU  - Paula Schoproni Cardoso
AU  - Marialva Siniglaglia
AU  - Tiago Falcon
AU  - André T. Brunetto
AU  - Algemir L. Brunetto
AU  - Caroline Brunetto de Farias
AU  - Michael D. Taylor
AU  - Carolina Nör
AU  - Vijay Ramaswamy
AU  - Rafael Roesler
TI  - HDAC and MAPK/ERK Inhibitors Cooperate to Reduce Viability and Stemness in Medulloblastoma
AID  - 10.1101/521393
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 521393
4099  - http://biorxiv.org/content/early/2020/01/30/521393.short
4100  - http://biorxiv.org/content/early/2020/01/30/521393.full
AB  - Medulloblastoma (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 markers BMI1 and CD133 are expressed in all molecular subgroups of MB. The HDAC inhibitor (HDACi) NaB reduced cell viability and expression of BMI1 and CD133 and increased acetylation in human MB cells. Enrichment analysis of genes associated with CD133 or BMI1 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.