Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Dreidax, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Bannert, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Henrich, Kai-Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Bender, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Oakes, Christopher C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindner, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulte, Johannes H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Duffy, David UNSPECIFIED orcid.org/0000-0002-6075-8855 UNSPECIFIED Schwarzl, Thomas UNSPECIFIED orcid.org/0000-0001-7697-7000 UNSPECIFIED Saadati, Maral UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehemann, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Benner, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfister, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Westermann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language ISLAND METHYLATOR PHENOTYPE; HIGH-THROUGHPUT ANALYSIS; D-DEPENDENT KINASES; INCREASED EXPRESSION; MICE LACKING; INK4 FAMILY; GENES; PATHWAY; IDENTIFICATION; AMPLIFICATION Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42005