Histone deacetylase (HDAC) inhibitors have been elucidated to induce hyperacetylation of histones resulting in transcriptionally active chromatin structure. Recently, inhibition of HDAC has represented a new strategy in human cancer therapy, since HDAC inhibitors induce growth arrest and apoptosis in some carcinoma cell lines. Adenosine-signaling has been shown to possess antiapoptotic properties through its receptor, e.g., the activation of A_2A receptor by the A_2A receptor agonist CGS21680 protects PC12 cells from oxidative stress-induced apoptosis. In this study, we tested the biological effect of the HDAC inhibitor trichostatin A (TSA) on PC12 cells, and found that treatment with TSA resulted in a significant decrease of the viability of PC12 cells in dose- and time-dependent manners. The cell death features revealed apoptosis accompanied by nuclear condensation and chromosomal DNA fragmentation. Western blot analysis showed that hyperacetylation of histone H3 occurred 6-10 hr after addition of TSA in PC12 cells. Accordingly, the phosphorylation of JNK was observed in a similar time course. 100 nM CGS21680 showed a counter effect on TSA-induced PC12 cell death when it was added 5-7 hr after addition of TSA. CGS21680 increased the survival signals, such as the phosphorylation of ERK1/2 and Akt, in PC12 cells. The protective effect of CGS21680 was inhibited by the A_2A selective antagonist CSC. Taken together, A_2A adenosine receptors are involved in the control of survival of PC12 cells and may contribute to regulation of cellular viability in response to epigenetic modulation. Buy this Article