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- Title
SET7/9 regulates cancer cell proliferation by influencing β-catenin stability.
- Authors
Changchun Shen; Donglai Wang; Xiangyu Liu; Bo Gu; Yipeng Du; Fu-Zheng Wei; Lin-Lin Cao; Boyan Song; Xiaopeng Lu; Qiaoyan Yang; Qian Zhu; Tianyun Hou; Meiting Li; Lina Wang; Haiying Wang; Ying Zhao; Yang Yang; Wei-Guo Zhu
- Abstract
β-Catenin, which is a key mediator of the wingless-integration site (Wnt)/β-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 β-catenin activity, the role of lysine methylation in β-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 and methylated β-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 β-catenin was monomethylated by SET7/9 at lysine residue 180. Methylated β-catenin was easily recognized by phosphokinase glycogen synthase kinase (GSK)-3β for degradation. Consistent with this finding, the mutated β-catenin (K180R) that cannot be methylated exhibited a longer half-life than did the methylated β-catenin. The consequent depletion of SET7/9 by shRNA or the mutation of the β-catenin (K180R) significantly enhanced the expression of Wnt/β-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/β-catenin signaling is regulated in response to oxidative stress.
- Subjects
CANCER cell proliferation; CATENINS; CELL determination; NEOPLASTIC cell transformation; LYSINE; METHYLATION
- Publication
FASEB Journal, 2015, Vol 29, Issue 10, p4313
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.15-273540