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 language | English |
|---|---|
| Pages (from-to) | 1502-1514 |
| Number of pages | 13 |
| Journal | Biochimica et Biophysica Acta - Gene Regulatory Mechanisms |
| Volume | 1859 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 1 2016 |
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Keywords
- DNA methylation
- Epigenetic network
- miRNA
- Neuroblastoma
ASJC Scopus subject areas
- Structural Biology
- Biophysics
- Biochemistry
- Molecular Biology
- Genetics
Cite this
Epigenetic dysregulation in neuroblastoma : A tale of miRNAs and DNA methylation. / Parodi, Federica; Carosio, Roberta; Ragusa, Marco; Di Pietro, Cinzia; Maugeri, Marco; Barbagallo, Davide; Sallustio, Fabio; Allemanni, Giorgio; Pistillo, Maria Pia; Casciano, Ida; Forlani, Alessandra; Schena, Francesco P.; Purrello, Michele; Romani, Massimo; Banelli, Barbara.
In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, Vol. 1859, No. 12, 01.12.2016, p. 1502-1514.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Epigenetic dysregulation in neuroblastoma
T2 - A tale of miRNAs and DNA methylation
AU - Parodi, Federica
AU - Carosio, Roberta
AU - Ragusa, Marco
AU - Di Pietro, Cinzia
AU - Maugeri, Marco
AU - Barbagallo, Davide
AU - Sallustio, Fabio
AU - Allemanni, Giorgio
AU - Pistillo, Maria Pia
AU - Casciano, Ida
AU - Forlani, Alessandra
AU - Schena, Francesco P.
AU - Purrello, Michele
AU - Romani, Massimo
AU - Banelli, Barbara
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - DNA methylation
KW - Epigenetic network
KW - miRNA
KW - Neuroblastoma
UR - http://www.scopus.com/inward/record.url?scp=84994884786&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994884786&partnerID=8YFLogxK
U2 - 10.1016/j.bbagrm.2016.10.006
DO - 10.1016/j.bbagrm.2016.10.006
M3 - Article
AN - SCOPUS:84994884786
VL - 1859
SP - 1502
EP - 1514
JO - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
JF - Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
SN - 1874-9399
IS - 12
ER -