Epigenetic dysregulation in neuroblastoma: A tale of miRNAs and DNA methylation

Federica Parodi, Roberta Carosio, Marco Ragusa, Cinzia Di Pietro, Marco Maugeri, Davide Barbagallo, Fabio Sallustio, Giorgio Allemanni, Maria Pia Pistillo, Ida Casciano, Alessandra Forlani, Francesco P. Schena, Michele Purrello, Massimo Romani, Barbara Banelli

Research output: Contribution to journalArticle

Abstract

In neuroblastoma, the epigenetic landscape is more profoundly altered in aggressive compared to lower grade tumors and the concomitant hypermethylation of many genes, defined as “methylator phenotype”, has been associated with poor outcome. DNA methylation can interfere with gene expression acting at distance through the methylation or demethylation of the regulatory regions of miRNAs. The multiplicity of miRNA targets may result in the simultaneous alteration of many biological pathways like cell proliferation, apoptosis, migration and differentiation. We have analyzed the methylation status of a set of miRNAs in a panel of neuroblastoma cell lines and identified a subset of hypermethylated and down-regulated miRNAs (miRNA 34b-3p, miRNA 34b-5p, miRNA34c-5p, and miRNA 124-2-3p) involved in the regulation of cell cycle, apoptosis and in the control of MYCN expression. These miRNAs share, in part, some of the targets whose expression is inversely correlated to the methylation and expression of the corresponding miRNA. To simulate the effect of the demethylation of miRNAs, we transfected the corresponding miRNA-mimics in the same cell lines and observed the down-regulation of a set of their target genes as well as the partial block of the cell cycle and the activation of the apoptotic pathway. The epigenetic alterations of miRNAs described in the present study were found also in a subset of patients at high risk of progression. Our data disclosed a complex network of interactions between epigenetically altered miRNAs and target genes, that could interfere at multiple levels in the control of cell homeostasis.

Original languageEnglish
Pages (from-to)1502-1514
Number of pages13
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1859
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

Keywords

  • DNA methylation
  • Epigenetic network
  • miRNA
  • Neuroblastoma

ASJC Scopus subject areas

  • Structural Biology
  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Parodi, F., Carosio, R., Ragusa, M., Di Pietro, C., Maugeri, M., Barbagallo, D., Sallustio, F., Allemanni, G., Pistillo, M. P., Casciano, I., Forlani, A., Schena, F. P., Purrello, M., Romani, M., & Banelli, B. (2016). Epigenetic dysregulation in neuroblastoma: A tale of miRNAs and DNA methylation. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1859(12), 1502-1514. https://doi.org/10.1016/j.bbagrm.2016.10.006