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Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.
- Source :
-
Molecular oncology [Mol Oncol] 2016 Feb; Vol. 10 (2), pp. 344-59. Date of Electronic Publication: 2015 Nov 07. - Publication Year :
- 2016
-
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.<br /> (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Adolescent
Adrenergic Neurons metabolism
Adult
Azacitidine analogs & derivatives
Azacitidine pharmacology
Cell Cycle
Cell Differentiation drug effects
Cell Line, Tumor
Child
Child, Preschool
CpG Islands genetics
DNA Methylation drug effects
Decitabine
Dopamine beta-Hydroxylase metabolism
Down-Regulation
Gene Knockdown Techniques
Humans
Infant
Infant, Newborn
N-Myc Proto-Oncogene Protein
Neuroblastoma genetics
Neuroblastoma metabolism
Nuclear Proteins metabolism
Oncogene Proteins metabolism
Prognosis
Promoter Regions, Genetic
RNA, Small Interfering metabolism
Repressor Proteins metabolism
Transcription Factor AP-2 genetics
Tretinoin pharmacology
Tyrosine 3-Monooxygenase metabolism
Up-Regulation
Young Adult
Adrenergic Neurons pathology
Neuroblastoma pathology
Transcription Factor AP-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0261
- Volume :
- 10
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular oncology
- Publication Type :
- Academic Journal
- Accession number :
- 26598443
- Full Text :
- https://doi.org/10.1016/j.molonc.2015.10.020