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

doi:10.18632/oncotarget.1991

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.

Highlights

Neuroblastoma, originating from precursor neuroblast cells in the sympathetic nervous system, is the most common malignancy of infancy and accounts for15% of childhood cancer-related death [1]
We have previously demonstrated that N-Myc and HDAC2 commonly suppress the expression of the cyclin G2 gene by forming a transcriptional repressor complex at an Sp1-binding site-enriched region of the www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget cyclin G2 gene promoter [6]
Bioinformatic analysis showed that the TP53INP1 gene promoter region is exceptionally enriched of Sp1-binding sites, while chromatin immunoprecipitation (ChIP) and luciferase assays demonstrated that N-Myc and HDAC2 both bind to the TP53INP1 gene promoter region to enhance TP53INP1 promoter activity

Summary

Introduction

Neuroblastoma, originating from precursor neuroblast cells in the sympathetic nervous system, is the most common malignancy of infancy and accounts for15% of childhood cancer-related death [1]. Amplification of the MYCN oncogene and consequent over-expression of the N-Myc oncoprotein occur in 20-30% of primary untreated neuroblastoma tissues, and are highly correlated with advanced disease stage as well as poor patient www.impactjournals.com/oncotarget prognosis [1, 2]. Myc oncoproteins induce tumor initiation and progression by modulating gene transcription. Myc dimerizes with MAX to form a Myc-MAX protein complex which directly binds to Myc-responsive element E-boxes at target gene promoters, leading to target gene transcription [3,4,5]. Myc oncoproteins repress gene transcription by forming transcriptional repressor complexes with histone deacetylases (HDACs) at Sp1binding sites of target gene promoters [6,7,8,9]. Identifying and further understanding the function of N-Myc target genes are important for developing better anticancer therapies

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