SET7/9 regulates cancer cell proliferation by influencing β-catenin stability

beta-Catenin, which is a key mediator of the wingless-integration site (Wnt)/beta-catenin signaling pathway, plays an important role in cell proliferation, cell fate determination, and tumorigenesis, by regulating the expression of a wide range of target genes. Although a variety of posttranslational modifications are involved in beta-catenin activity, the role of lysine methylation in beta-catenin activity is largely unknown. In this study, su(var) 3-9, enhancer-of-zeste, trithorax (SET) domain-containing protein 7 (SET7/9), a lysine methyltransferase, interacted with andmethylated beta-catenin, as demonstrated both in vitro and in vivo. The interaction and methylation were significantly enhanced in response to H2O2 stimulation. A mutagenesis assay and mass spectrometric analyses revealed that beta-catenin was monomethylated by SET7/9 at lysine residue 180. Methylated beta-catenin was easily recognized by phosphokinase glycogen synthase kinase (GSK)-3 beta for degradation. Consistent with this finding, the mutated beta-catenin (K180R) that cannot be methylated exhibited a longer half-life than did the methylated beta-catenin. The consequent depletion of SET7/9 by shRNA or the mutation of the beta-catenin (K180R) significantly enhanced the expression of Wnt/beta-catenin target genes such as c-myc and cyclin D1 and promoted the growth of cancer cells. Together, these results provide a novel mechanism by which Wnt/beta-catenin signaling is regulated in response to oxidativ stress.