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

Abstract

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.

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Funding

This manuscript has been released as a pre-print at bioRxiv: https://www.biorxiv.org/content/10.1101/521393v1. This research was supported by the National Council for Scientific and Technological Development (CNPq; Grant Numbers 303276/2013-4 and 409287/2016-4 to R.R., Grant Number 201001/2014-4 to C.N., and graduate fellowship to M.C.J.); PRONON/Ministry of Health, Brazil (number 25000.162.034/2014-21); the Children’s Cancer Institute (ICI); the Rio Grande do Sul State Research Foundation (FAPERGS; Grant Number 17/2551-0001 071-0 to R.R.); the Coordination for the Improvement of Higher Education Personnel (CAPES); and the Clinical Hospital institutional research fund (FIPE/HCPA). T.F. is supported by Programa Nacional de Pós-Doutorado (PNPD, CAPES/HCPA, Grant Number: 88887.160608/2017-00). C.N. is also supported by the William Donald Nash fellowship from the Brain Tumour Foundation of Canada. V.R. is supported by operating funds from the Canadian Institutes for Health Research, the American Brain Tumor Association, and the Brain Tumour Foundation of Canada. M.D.T. is supported by the National Institutes of Health, the Pediatric Brain Tumour Foundation, the Terry Fox Research Institute, the Canadian Institutes of Health Research, the Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, Genome Canada, Genome BC, the Ontario Institute for Cancer Research, and the Canadian Cancer Society Research Institute.

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Correspondence to Rafael Roesler.

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da Cunha Jaeger, M., Ghisleni, E.C., Cardoso, P.S. et al. HDAC and MAPK/ERK Inhibitors Cooperate To Reduce Viability and Stemness in Medulloblastoma. J Mol Neurosci (2020). https://doi.org/10.1007/s12031-020-01505-y

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Keywords

  • Histone deacetylase
  • Extracellular-regulated kinase
  • Stem cells
  • Medulloblastoma
  • Brain tumor