Our data show that SMYD3 is upregulated in CRC and independently predicts poor survival; that SMYD3 promotes EMT, invasion and liver colonization; that CDCP1 is a direct chromatin target activated by SMYD3-dependent H3K4me3; and that CDCP1 is required for SMYD3-driven metastatic traits and for paracrine CAF activation. The gene discussed is SMYD3; the disease is colorectal carcinoma.