Combinatorial silencing of Ring1B and EZH2 depleted H2AK119Ub1 and H3K27Me3 in pancreatic cancer cells, enhanced HOX gene derepression, and inhibited tumor cell growth both in vitro and in vivo, indicating the potential link between H2AK119Ub1 and H3K27Me3. The gene discussed is RNF2; the disease is familial pancreatic carcinoma.