Apicidin sensitizes pancreatic cancer cells to gemcitabine by epigenetically regulating MUC4 expression. 
Mucin 4 (MUC4) has been linked to resistance to gemcitabine in pancreatic cancer cells.  The aim of the present study was to assess whether epigenetic control of MUC4 expression can sensitize pancreatic cancer cells to gemcitabine treatment.  A 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened for anti-proliferative activity against the MUC4(+) gemcitabine-resistant pancreatic cancer cell line Capan-1, followed by high-content screening of protein expression.  Apicidin, a histone deacetylase inhibitor, showed the greatest anti-proliferative activity with a lethal dose 50 (LD50) value of 5.17 μM. Apicidin significantly reduced the expression of MUC4 and its transcription factor hepatocyte nuclear factor 4α.  Combined treatment with a sub-therapeutic concentration of apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells.  Apicidin appears to be a novel anti-proliferative agent against pancreatic cancer cells that may reverse chemoresistance by epigenetically regulating MUC4 expression.