TY  - JOUR
AU  - Dreidax, Daniel
AU  - Bannert, Steffen
AU  - Henrich, Kai-Oliver
AU  - Schröder, Christina
AU  - Bender, Sebastian
AU  - Oakes, Christopher C
AU  - Lindner, Sven
AU  - Schulte, Johannes H
AU  - Duffy, David
AU  - Schwarzl, Thomas
AU  - Saadati, Maral
AU  - Ehemann, Volker
AU  - Benner, Axel
AU  - Pfister, Stefan
AU  - Fischer, Matthias
AU  - Westermann, Frank
TI  - p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas.
JO  - Human molecular genetics
VL  - 23
IS  - 25
SN  - 1460-2083
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2017-00480
SP  - 6826 - 6837
PY  - 2014
AB  - 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.
KW  - Antimetabolites, Antineoplastic (NLM Chemicals)
KW  - CDKN2D protein, human (NLM Chemicals)
KW  - Cyclin-Dependent Kinase Inhibitor p19 (NLM Chemicals)
KW  - MYCN protein, human (NLM Chemicals)
KW  - N-Myc Proto-Oncogene Protein (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - Oncogene Proteins (NLM Chemicals)
KW  - Tretinoin (NLM Chemicals)
KW  - decitabine (NLM Chemicals)
KW  - Azacitidine (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25104850
DO  - DOI:10.1093/hmg/ddu406
UR  - https://inrepo02.dkfz.de/record/119889
ER  -