Open AccessTranscription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma
Author(s) -
Ikram Fakhera,
Ackermann Sandra,
Kahlert Yvonne,
Volland Ruth,
Roels Frederik,
Engesser Anne,
Hertwig Falk,
Kocak Hayriye,
Hero Barbara,
Dreidax Daniel,
Henrich Kai-Oliver,
Berthold Frank,
Nürnberg Peter,
Westermann Frank,
Fischer Matthias
Publication year - 2016
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2015.10.020
Subject(s) - neuroblastoma , biology , gene knockdown , transcription factor , cancer research , retinoic acid , cellular differentiation , microbiology and biotechnology , gene , genetics , cell culture
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.