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Hum Mol Genet. 2014 Dec 20;23(25):6826-37. doi: 10.1093/hmg/ddu406. Epub 2014 Aug 7.

p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas.

Author information

1
Division of Neuroblastoma Genomics.
2
Division of Pediatric Neurooncology.
3
Division of Epigenomics and Cancer Risk Factors.
4
Department of Pediatric Oncology and Hematology, University Children's Hospital, Essen, Germany.
5
Systems Biology Ireland, Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Ireland.
6
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Department of Pathology, University of Heidelberg, Heidelberg, Germany and.
8
Department of Pediatric Oncology and Center for Molecular Medicine Cologne (CMMC), University Children's Hospital, Cologne, Germany.
9
Division of Neuroblastoma Genomics f.westermann@dkfz.de.

Abstract

Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is a crucial determinant of neuroblastoma cell malignancy. Here we identify neuroblastoma-suppressive functions of the p19-INK4d CDK inhibitor and uncover mechanisms of its repression in high-risk neuroblastomas. Reduced p19-INK4d expression was associated with poor event-free and overall survival and neuroblastoma risk factors including amplified MYCN in a set of 478 primary neuroblastomas. High MYCN expression repressed p19-INK4d mRNA and protein levels in different neuroblastoma cell models with conditional MYCN expression. MassARRAY and 450K methylation analyses of 105 primary neuroblastomas uncovered a differentially methylated region within p19-INK4d. Hypermethylation of this region was associated with reduced p19-INK4d expression. In accordance, p19-INK4d expression was activated upon treatment with the demethylating agent, 2'-deoxy-5-azacytidine, in neuroblastoma cell lines. Ectopic p19-INK4d expression decreased viability, clonogenicity and the capacity for anchorage-independent growth of neuroblastoma cells, and shifted the cell cycle towards the G1/0 phase. p19-INK4d also induced neurite-like processes and markers of neuronal differentiation. Moreover, neuroblastoma cell differentiation, induced by all-trans retinoic acid or NGF-NTRK1-signaling, activated p19-INK4d expression. Our findings pinpoint p19-INK4d as a neuroblastoma suppressor and provide evidence for MYCN-mediated repression and for epigenetic silencing of p19-INK4d by DNA hypermethylation in high-risk neuroblastomas.

PMID:
25104850
DOI:
10.1093/hmg/ddu406
[Indexed for MEDLINE]

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