title: Histone deacetylase 2 and N-Myc reduce p53 protein phosphorylation at serine 46 by repressing gene transcription of tumor protein 53-induced nuclear protein 1.
abstract: Myc oncoproteins and histone deacetylases (HDACs) exert oncogenic effects by modulating gene transcription. Paradoxically, N-Myc induces p53 gene expression. Tumor protein 53-induced nuclear protein 1 (TP53INP1) phosphorylates p53 protein at serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes and programmed cell death. Here we aimed to identify the mechanism through which N-Myc overexpressing p53 wild-type neuroblastoma cells acquired resistance to apoptosis. TP53INP1 was found to be one of the genes most significantly repressed by HDAC2 and N-Myc according to Affymetrix microarray gene expression datasets. HDAC2 and N-Myc reduced TP53INP1 gene expression by direct binding to the TP53INP1 gene promoter, leading to transcriptional repression of TP53INP1, p53 protein de-phosphorylation at serine 46, neuroblastoma cell proliferation and survival. Moreover, low levels of TP53INP1 expression in human neuroblastoma tissues correlated with high levels of N-Myc expression and poor patient outcome, and the BET bromodomain inhibitors JQ1 and I-BET151 reduced N-Myc expression and reactivated TP53INP1 expression in neuroblastoma cells. These findings identify TP53INP1 repression as an important co-factor for N-Myc oncogenesis, and provide further evidence for the potential application of BET bromodomain inhibitors in the therapy of N-Myc-induced neuroblastoma.
authors: Children's Cancer Institute Australia for Medical Research, Sydney, Australia; School of Biotechnology and Biomolecular Sciences, UNSW Science, University of New South Wales, Sydney, Australia.
authors: Jeyran
authors: J
authors: Shahbazi
authors: Christopher J
authors: CJ
authors: Scarlett
authors: Murray D
authors: MD
authors: Norris
authors: Bing
authors: B
authors: Liu
authors: Michelle
authors: M
authors: Haber
authors: Andrew E
authors: AE
authors: Tee
authors: Alice
authors: A
authors: Carrier
authors: Andrew V
authors: AV
authors: Biankin
authors: Wendy B
authors: WB
authors: London
authors: Glenn M
authors: GM
authors: Marshall
authors: Richard B
authors: RB
authors: Lock
authors: School of Women's and Children's Health, UNSW Medicine, University of New South Wales, Sydney, Australia.
authors: Tao
authors: T
authors: Liu
mesh_terms: D017209:Apoptosis; D015331:Cohort Studies; D056464:Histone Deacetylase 2 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D056464:Histone Deacetylase 2