%0 Journal Article
%A Dreidax, Daniel
%A Bannert, Steffen
%A Henrich, Kai-Oliver
%A Schröder, Christina
%A Bender, Sebastian
%A Oakes, Christopher C
%A Lindner, Sven
%A Schulte, Johannes H
%A Duffy, David
%A Schwarzl, Thomas
%A Saadati, Maral
%A Ehemann, Volker
%A Benner, Axel
%A Pfister, Stefan
%A Fischer, Matthias
%A Westermann, Frank
%T p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas.
%J Human molecular genetics
%V 23
%N 25
%@ 1460-2083
%C Oxford
%I Oxford Univ. Press
%M DKFZ-2017-00480
%P 6826 - 6837
%D 2014
%X 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.
%K Antimetabolites, Antineoplastic (NLM Chemicals)
%K CDKN2D protein, human (NLM Chemicals)
%K Cyclin-Dependent Kinase Inhibitor p19 (NLM Chemicals)
%K MYCN protein, human (NLM Chemicals)
%K N-Myc Proto-Oncogene Protein (NLM Chemicals)
%K Nuclear Proteins (NLM Chemicals)
%K Oncogene Proteins (NLM Chemicals)
%K Tretinoin (NLM Chemicals)
%K decitabine (NLM Chemicals)
%K Azacitidine (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:25104850
%R 10.1093/hmg/ddu406
%U https://inrepo02.dkfz.de/record/119889