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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.

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Division of Neuroblastoma Genomics.
Division of Pediatric Neurooncology.
Division of Epigenomics and Cancer Risk Factors.
Department of Pediatric Oncology and Hematology, University Children's Hospital, Essen, Germany.
Systems Biology Ireland, Conway Institute of Biomolecular and Biomedical Research and School of Medicine and Medical Science, University College Dublin, Ireland.
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Pathology, University of Heidelberg, Heidelberg, Germany and.
Department of Pediatric Oncology and Center for Molecular Medicine Cologne (CMMC), University Children's Hospital, Cologne, Germany.
Division of Neuroblastoma Genomics


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.

[Indexed for MEDLINE]

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