Here we showed that NSD3 silencing (by targeted shRNA) or KO (using CRISPR/Cas9 method) in pancreatic cancer cells potently inhibited H3K36m2 and expression of these oncogenic genes (Prkaa2, Myc, Irgm1, Adam12, and Notch3). The gene discussed is PRKAA2; the disease is familial pancreatic carcinoma.