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- Title
p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas.
- Authors
Dreidax, Daniel; Bannert, Steffen; Henrich, Kai-Oliver; Schröder, Christina; Bender, Sebastian; Oakes, Christopher C.; Lindner, Sven; Schulte, Johannes H.; Duffy, David; Schwarzl, Thomas; Saadati, Maral; Ehemann, Volker; Benner, Axel; Pfister, Stefan; Fischer, Matthias; Westermann, Frank
- Abstract
Uncontrolled cell cycle entry, resulting from deregulated CDK-RB1-E2F pathway activity, is acrucial 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. Mass ARRAY 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-INK4dexpression. In accordance, p19-INK4d expression was activated upon treatment with the demethylating agent, 2-deoxy-5-azacy-tidine, 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.
- Publication
Human Molecular Genetics, 2012, Vol 21, Issue 25, p1
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddu406