INTRODUCTION: Histone deacetylases (HDACs) are commonly dysregulated in 
pancreatic adenocarcinoma (PA) and have a central role in the development and 
progression of the disease. HDAC is a family of enzymes involved in 
deacetylation of lysine residues on histone and non-histone proteins. 
Deacetylation of histone proteins leads to compaction of the DNA/histone complex 
resulting in inhibition of gene expression. Deacetylation of non-histone 
proteins can affect the stability and function of key proteins leading to 
dysregulation of cellular signaling pathways. HDAC inhibitors have been shown to 
potentiate the antiproliferative and proapoptotic effects of several cytotoxic 
agents, in vitro and in vivo PA xenograft models.
AREAS COVERED: The areas covered include the biology and function of the HDAC 
isoenzymes and their significant role in multiple oncogenic pathways in PA. 
Preclinical and clinical trials evaluating HDAC inhibitors are also reviewed.
EXPERT OPINION: Despite discouraging early phase clinical trials evaluating HDAC 
inhibitors in PA, this strategy deserves further evaluation guided by better 
preclinical studies in identifying the role of specific HDAC isoenzyme 
inhibitors in PA. Evaluation of the effects of HDAC inhibitors on PA stem cell 
function and epithelial to mesenchymal transformation is also an evolving area 
that holds future potential for these agents. Such preclinical studies will 
yield insight into the functionality of HDAC isoenzymes, which can then be 
translated into rationally designed clinical trials. One such strategy could 
focus on HDAC inhibition employed in combination with proteasome inhibition 
targeting the aggresome pathway in PA.