Abstract Epithelial-to-Mesenchymal Transition (EMT) is a tumor cell remodeling process that drives progression of several epithelial solid tumors including pancreatic tumors. Transforming growth factor (TGF) β signaling is a key promoter of EMT pathway and remains an attractive target for curtailing tumor progression. Here we present a strategy for investigating inhibitors of TGFβ signaling in pancreatic cancer via reprograming of miRNAs. We find a carbocyclic adenosine analog and histone methyl transferase inhibitor, 3-deazaneplanocin A (DZNep) to significantly attenuate the TGFβ signaling induced EMT characteristics in pancreatic ductal adenocarcinoma (PDAC). Specifically, we find DZNep treatment to restore expression of selective epigenetically silenced miRNAs (mir-663a, miR-4787-5p, and miR-202) that inhibit endogenous TGFβ1 ligand and receptor expression via RNA interference. Consequently, DZNep significantly attenuated both exogenous and endogenous TGFβ-induced EMT response. Lentiviral overexpression of mir-663a, miR-4787-5p or miR-202 reduced tumor cellular proliferation and EMT phenotypic characteristics similar to DZNep in cultured pancreatic cancer cells, whereas locked nucleic acids inhibition of miRNAs abrogated such effects. In an orthotopic pancreatic cancer mouse model, DZNep and all three miRs reduced overall tumor burden in pancreas and metastatic load in liver, lungs and spleen. Together, these findings suggest epigenetic reprograming of miRNAs by synthetic histone methylation reversal agents as a potentially viable approach for attenuating TGFβ signaling pathway involved in pancreatic cancer progression. Citation Format: Hardik R. Mody, Rajgopal Govindarajan. Pharmacological inhibition of histone methylation attenuates TGFβ induced EMT characteristics in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3421. doi:10.1158/1538-7445.AM2017-3421