The impact of amyloid precursor protein signalling and histone deacetylase inhibition on neprilysin expression in human prostate cells

Abstract

The zinc metallopeptidase, neprilysin (NEP), is an endothelin-1 degrading enzyme whose expression is extensively downregulated in prostate cancer. The expression of NEP in neuronal cells is regulated by intramembrane proteolysis of the amyloid precursor protein (APP) through its intracellular domain (AICD) facilitating histone acetylation of the NEP promoter and gene transcription. The present study has examined whether similar mechanisms operate in prostate cell lines. The expression of APP and its processing enzymes (β- and γ-secretases) was examined in a number of prostate cell lines, and the effect of γ-secretase inhibition was explored on NEP expression and activity. The potential interaction of AICD with the NEP promoter was examined by chromatin immunoprecipitation. Our results indicated that all key components involved in APP processing were expressed in prostate cancer cell lines but suppression of AICD production using a γ-secretase inhibitor did not decrease NEP expression and activity, and no direct AICD-NEP promoter interaction could be detected. However, histone deacetylase inhibitors (valproate and trichostatin A) caused a 2- to 3-fold increase in NEP expression in PC-3 cells, and combinatorial treatment with the DNA demethylating agent, AzaC, further increased NEP expression levels. Although AICD is detectable in prostate cell lines, it does not appear to regulate NEP by AICD-mediated signalling. Apart from promoter de-methylation, the data suggest that histone acetylation may facilitate partial re-activation of NEP expression in advanced prostate cancer cells. Upregulation of this tumour-suppressing protein may provide a novel therapeutic strategy in prostate cancer.