Gemcitabine has been a first line therapeutic agent for pancreatic ductal adenocarcinoma (PDAC); however, the acquisition of resistance to gemcitabine remains a major challenge. Here, we investigated the metabolite profiles by liquid chromatography mass spectrometry between gemcitabine resistant PDAC and parental PDAC cells, and found that lactic acid amount and lactate dehydrogenase activity were increased in gemcitabine resistant PDAC cells. We observed the elevated lactate dehydrogenase A (LDHA) expression significantly correlated with recurrent pancreatic cancer patients following gemcitabine treatment and with cancer stem cell (CSC) properties. We further identified that FOXO3a induced miR4259 directly targeted the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer. Our findings provide evidence of an underlying epigenetic regulation of LDHA by FOXO3a/miR4259, which appears to be involved in cancer stemness and the chemoresistance of pancreatic cancer.
