Universität zu Köln

Ikram, Fakhera ORCID: 0000-0001-7796-4746, Ackermann, Sandra ORCID: 0000-0002-5869-7344, Kahlert, Yvonne, Volland, Ruth, Roels, Frederik, Engesser, Anne, Hertwig, Falk ORCID: 0000-0003-4784-6516, Kocak, Hayriye, Hero, Barbara, Dreidax, Daniel, Henrich, Kai-Oliver, Berthold, Frank, Nuernberg, Peter, Westermann, Frank and Fischer, Matthias (2016). Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma. Mol. Oncol., 10 (2). S. 344 - 360. OXFORD: ELSEVIER SCI LTD. ISSN 1878-0261

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Abstract

Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ikram, Fakhera UNSPECIFIED orcid.org/0000-0001-7796-4746 UNSPECIFIED Ackermann, Sandra UNSPECIFIED orcid.org/0000-0002-5869-7344 UNSPECIFIED Kahlert, Yvonne UNSPECIFIED UNSPECIFIED UNSPECIFIED Volland, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED Roels, Frederik UNSPECIFIED UNSPECIFIED UNSPECIFIED Engesser, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Hertwig, Falk UNSPECIFIED orcid.org/0000-0003-4784-6516 UNSPECIFIED Kocak, Hayriye UNSPECIFIED UNSPECIFIED UNSPECIFIED Hero, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Dreidax, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Henrich, Kai-Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Berthold, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Westermann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-286564
DOI:	10.1016/j.molonc.2015.10.020
Journal or Publication Title:	Mol. Oncol.
Volume:	10
Number:	2
Page Range:	S. 344 - 360
Date:	2016
Publisher:	ELSEVIER SCI LTD
Place of Publication:	OXFORD
ISSN:	1878-0261
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HIGH-RISK NEUROBLASTOMA; TUMOR-SUPPRESSOR GENES; RETINOIC ACID; FACTOR AP-2; 13-CIS-RETINOIC ACID; MONOCLONAL-ANTIBODY; FACTOR AP-2-BETA; RANK STATISTICS; POOR-PROGNOSIS; BREAST-CANCER Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28656