During cancer development, tumor suppressor genes were silenced by promoter 
methylation or histone deacetylation. Histone deacetylases (HDACs) are important 
to maintain histone deacetylation. HDAC inhibitors (HDACis) were thus proposed 
as a new therapeutic approach to cancer. The current study aims to understand 
the effect and molecular mechanisms of HDACis on gastric cancer cells. 
Trichostatin A (TSA) significantly inhibited the growth of gastric cancer cells 
by inducing apoptosis. Gene profiling results showed PUMA (p53 upregulated 
modulator of apoptosis) as one of 122 genes upregulated in TSA-treated gastric 
cancer cells. PUMA was downregulated in gastric cancer cell lines and primary 
gastric carcinoma tissues. Patients with low PUMA expression had significant 
decreases in overall survival (HR, 2.04; p = 0.047). Ectopic PUMA expression 
inhibited the growth of gastric cancer cells while PUMA depletion promoted 
cellular growth. The knockdown of HDAC3 but not other HDACs upregulated PUMA 
expression. HDAC3 could bind to PUMA promoter, which was abrogated after TSA 
treatment. In contrast to TSA and SB, HDAC3 siRNA failed to upregulate p53 
expression but promoted the interaction of p53 with PUMA promoter. In summary, 
proapoptotic PUMA was downregulated in gastric cancer and its mRNA expression 
level is a valuable prognosis factor for gastric cancer. HDAC3 is important to 
downregulate PUMA expression in gastric cancer and HDACis, like TSA, promoted 
PUMA expression through stabilizing p53 in addition to HDAC3 inhibition. In 
combination with chemotherapy, targeting HDAC3 might be a promising strategy to 
induce apoptosis of gastric cancer cells.