title: Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells.
abstract: Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system and accounts for approximately 15% of all pediatric cancer-related deaths. To newly identify gene(s) implicated in the progression of neuroblastoma, we investigated aberrantly methylated genomic regions in mouse skin tumors. Previously, we reported that TFAP2E, a member of activator protein-2 transcription factor family, is highly methylated within its intron and its expression is strongly suppressed in mouse skin tumors compared with the normal skin. In the present study, we analyzed public data of neuroblastoma patients and found that lower expression levels of TFAP2E are significantly associated with a shorter survival. The data indicate that TFAP2E acts as a tumor suppressor of neuroblastoma. Consistent with this notion, TFAP2E-depleted neuroblastoma NB1 and NB9 cells displayed a substantial resistance to DNA damage arising from adriamycin (ADR), cisplatin (CDDP) and ionizing radiation (IR). Silencing of TFAP2E caused a reduced ADR-induced proteolytic cleavage of caspase-3 and PARP. Of note, compared with the untransfected control cells, ADR-mediated stimulation of CDK inhibitor p21WAF1 was markedly upregulated in TFAP2E‑knocked down cells. Therefore, our present findings strongly suggest that TFAP2E has a pivotal role in the regulation of DNA damage response in NB cells through the induction of p21WAF1.
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Hoshi
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ishizuka
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Nagasaki-Maeoka
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yoshizawa
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Uekusa
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawashima
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Kiminobu
authors.initials: K
authors.lastname: Sugito
authors.affiliation: Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.affiliation: Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Soma
authors.affiliation: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
authors.affiliation: Department of Pediatric Surgery, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Tsugumichi
authors.initials: T
authors.lastname: Koshinaga
authors.affiliation: Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-0032, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Fujiwara
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D050656:Transcription Factor AP-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D004317:Doxorubicin