title: Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.
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.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany; Cologne Center for Genomics (CCG), University of Cologne, Germany.
authors.forename: Fakhera
authors.initials: F
authors.lastname: Ikram
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ackermann
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kahlert
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Volland
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roels
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Engesser
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hertwig
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Hayriye
authors.initials: H
authors.lastname: Kocak
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.affiliation: Division Neuroblastoma Genomics (B087), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dreidax
authors.affiliation: Division Neuroblastoma Genomics (B087), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Kai-Oliver
authors.initials: KO
authors.lastname: Henrich
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany; Cologne Center for Genomics (CCG), University of Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Division Neuroblastoma Genomics (B087), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany; Max Planck Institute for Metabolism Research, Cologne, Germany. Electronic address: matthias.fischer@uk-koeln.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
mesh_terms: D000293:Adolescent; D059331:Adrenergic Neurons / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult; D000099229:RE1-Silencing Transcription Factor
chemical_list: D001374:Azacitidine; D000077209:Decitabine; D004299:Dopamine beta-Hydroxylase; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D050656:Transcription Factor AP-2; D014212:Tretinoin; D014446:Tyrosine 3-Monooxygenase; D000099229:RE1-Silencing Transcription Factor; C459801:MYCN protein, human; C493677:TFAP2B protein, human
keywords: Differentiation; Neuroblastoma; Prognostic marker; Retinoic acid; TFAP2B