Simultaneous silencing of Ring1B and EZH2 via shRNA depleted H2AK119Ub1 and H3K27Me3 in the pancreatic cancer cells PanC1 and AsPC1, enhanced HOX gene derepression, and inhibited tumor cell growth in vitro and in tumor xenograft models. The gene discussed is RNF2; the disease is familial pancreatic carcinoma.