Quercetin enhances the antitumor activity of trichostatin A through up-regulation of p300 protein expression in p53 null cancer cells

In the present study, we investigated the p53-independent mechanism by which quercetin (Q) increased apoptosis in human lung cancer H1299 cells exposed to trichostatin A (TSA), a histone deacetylase inhibitor. We also investigated the role of Q in increasing the acetylation of histones H3 and H4 and the possible mechanism. Q at 5 mu M significantly increased apoptosis by 88% in H1299 cells induced by TSA at 72 h. Q also significantly increased TSA-induced death receptor 5 (DR5) mRNA and protein expression as well as caspase-10/3 activities in H1299 cells. Transfection of DR5 siRNA into H1299 cells significantly diminished the enhancing effects of Q on TSA-induced apoptosis. Furthermore, TSA in combination with Q rather than TSA alone significantly increased p300 expression. Transfection of p300 siRNA in H1299 cells significantly diminished the increase of histone H3/H4 acetylation, DR5 protein expression, caspase-10/3 activity and apoptosis induced by Q. In addition, similar effects of Q were observed when Q was combined with vorinostat, another FDA-approved histone deacetylase inhibitor. These data suggest that the up-regulation of p300 expression, which in turn increases histone acetylation and DR5 expression, plays an important role in the enhancing effect of Q on TSA/vorinostat-induced apoptosis in H1299 cells.