Myc oncoproteins induce the initiation and promote the progression of malignancies by modulating gene transcription. We have found that up-regulation of the histone deacetylase HDAC2 contributes to N-Myc-induced cell proliferation in p53-mutant neuroblastoma cells. However, it is unknown whether and how HDAC2 modulates p53 activity and consequently neuroblastoma cell proliferation.
Our previous Affymetrix microarray studies revealed that N-Myc siRNA and HDAC2 siRNA commonly up-regulated the expression of a subset of genes including p53 induced nuclear protein 1 (TP53INP1). TP53INP1 is a tumour suppressor gene which phosphorylates p53 protein at Serine 46, leading to enhanced p53 activity, transcriptional activation of p53 target genes, cell growth arrest and/or apoptosis.
In this study, we demonstrated that knocking down N-Myc or HDAC2 expression with siRNAs commonly up-regulated TP53INP1 gene and protein expression and enhanced p53 protein phosphorylation at Serine 46 in Kelly and SK-N-BE(2) neuroblastoma cells. Consistently, knocking down TP53INP1 expression with siRNAs reduced p53 protein phosphorylation at Serine 46. Furthermore, repression of TP53INP1 gene expression blocked HDAC2 siRNA-mediated neuroblastoma cell growth arrest.
Taken together, our data suggest that HDAC2 contributes to neuroblastoma cell proliferation by repressing TP53INP1 gene expression, leading to p53 protein de-phosphorylation and inactivation.