ARID1A as a subunit of SWI/SNF chromatin complexes is frequently mutated in human pancreatic cancer, however its exact role in pancreatic tumorigenesis remain unclear. In this study, we investigated the effects of ARID1A loss on human pancreatic epithelial cell lines HPNE, BxPC-3 with KRAS mutant (KRAS(G12D) expression. We found that ARID1A knockdown promoted cell proliferation and colony formation in cooperation with active mutant KRAS(G12D). Function assay revealed that ARID1A knockdown accelerated cell cycle progression, and repressed KRAS(G12D)-induced cell senescence. Transcriptome analysis revealed ARID1A knockdown led to miR-503 upregulation. CDKN2A was identified as a target of miR-503, which contributes to cell senescence. Thus, our data suggests that ARID1A deficiency promote KRAS(G12D)-driven pancreatic tumorigenesis through miR-503/CDKN2A-mediated senescence. (C) 2017 Elsevier Inc. All rights reserved.