title: MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4.
abstract: Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4) has been reported to be a direct transcriptional target of MYC. We show for the first time that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome. siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells led to inhibition of cell proliferation and migration. Chromatin immunoprecipitation assay demonstrated that TFAP4 expression is positively regulated by MYCN. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study suggests a regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying potential therapeutic targets for aggressive forms of this disease.
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Xue
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Denise M T
authors.initials: DM
authors.lastname: Yu
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Gherardi
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Koach
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Milazzo
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Gamble
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valli
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Russell
authors.affiliation: Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.|Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.|CIRI Health Sciences and Technologies University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Perini
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Haber
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.|University of New South Wales Centre for Childhood Cancer Research, Sydney, Australia.
authors.forename: Murray D
authors.initials: MD
authors.lastname: Norris
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000071447:N-Myc Proto-Oncogene Protein; D014157:Transcription Factors; C055473:enhancer-binding protein AP-4
keywords: MYCN oncogene; TFAP4; cancer; cell migration; neuroblastoma