Research Papers:

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

Jeyran Shahbazi, Christopher J. Scarlett, Murray D. Norris, Bing Liu, Michelle Haber, Andrew E. Tee, Alice Carrier, Andrew V. Biankin, Wendy B. London, Glenn M. Marshall, Richard B. Lock and Tao Liu _

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Oncotarget. 2014; 5:4257-4268. https://doi.org/10.18632/oncotarget.1991

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Jeyran Shahbazi1,2, Christopher J. Scarlett3,4, Murray D. Norris1, Bing Liu1, Michelle Haber1, Andrew E. Tee1, Alice Carrier5, Andrew V. Biankin4,6, Wendy B. London7, Glenn M. Marshall1,8, Richard B. Lock1 and Tao Liu1,9

1 Children’s Cancer Institute Australia for Medical Research, Sydney, Australia

2 School of Biotechnology and Biomolecular Sciences, UNSW Science, University of New South Wales, Sydney, Australia

3 School of Environmental and Life Sciences, University of Newcastle, Ourimbah, Australia

4 Cancer Research Program, Garvan Institute of Medical Research, Sydney, Australia

5 INSERM, U1068, CRCM ‘Stress cellulaire’, Marseille F-13009, France

6 Wolfson Wohl Cancer Research Centre, University of Glasgow and Glasgow Royal Infirmary, Glasgow, United Kingdom;

7 Children’s Oncology Group Statistics and Data Center and Boston Children’s Hospital/Dana-Farber Cancer Institute, Boston, MA, USA

8 Kids Cancer Centre, Sydney Children’s Hospital, Sydney, Australia

9 School of Women’s and Children’s Health, UNSW Medicine, University of New South Wales, Sydney, Australia


Tao Liu, email:

Keywords: N-Myc, HDAC2, p53, TP53INP1

Received: January 22, 2014 Accepted: May 18, 2014 Published: May 20, 2014


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.

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