Dreidax, Daniel, Bannert, Steffen, Henrich, Kai-Oliver, Schroeder, Christina, Bender, Sebastian, Oakes, Christopher C., Lindner, Sven, Schulte, Johannes H., Duffy, David ORCID: 0000-0002-6075-8855, Schwarzl, Thomas ORCID: 0000-0001-7697-7000, Saadati, Maral, Ehemann, Volker, Benner, Axel, Pfister, Stefan, Fischer, Matthias and Westermann, Frank (2014). p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas. Hum. Mol. Genet., 23 (25). S. 6826 - 6838. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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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-/NK4dexpression. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dreidax, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bannert, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henrich, Kai-OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bender, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oakes, Christopher C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, Johannes H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duffy, DavidUNSPECIFIEDorcid.org/0000-0002-6075-8855UNSPECIFIED
Schwarzl, ThomasUNSPECIFIEDorcid.org/0000-0001-7697-7000UNSPECIFIED
Saadati, MaralUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ehemann, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benner, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfister, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-420050
DOI: 10.1093/hmg/ddu406
Journal or Publication Title: Hum. Mol. Genet.
Volume: 23
Number: 25
Page Range: S. 6826 - 6838
Date: 2014
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2083
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ISLAND METHYLATOR PHENOTYPE; HIGH-THROUGHPUT ANALYSIS; D-DEPENDENT KINASES; INCREASED EXPRESSION; MICE LACKING; INK4 FAMILY; GENES; PATHWAY; IDENTIFICATION; AMPLIFICATIONMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42005

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