In our study, we demonstrated that EHMT2 is implicated in the regulation of Wnt–β-catenin signaling pathway in HCC by several lines of evidence: (1) EHMT2 directly binds to the promoter of APC in HepG2, Hep3B and Huh1; (2) EHMT2 mediates H3K9me2 of APC promotor; (3) EHMT2 promotes the expression of APC both in mRNA and protein levels; (4) the functions of EHMT2 are largely abolished by deletion of APC in Hep3B and Huh1 cells. Here, APC is linked to hepatocellular carcinoma.