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

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.

SETD7 Controls Intestinal Regeneration and Tumorigenesis by Regulating Wnt/β-Catenin and Hippo/YAP Signaling

“…Thus, in addition to established PTMs such as phosphorylation and ubiquitination, we propose that methylation of non-histone proteins is an important regulator of signal transduction, which is in line with several recent studies (Fang et al, 2014;Kim et al, 2013;Mazur et al, 2014). Indeed, a recent study identified a role for SETD7 in the direct methylation of b-catenin (Shen et al, 2015). It was proposed that SETD7dependent methylation of b-catenin was required for optimal degradation in response to oxidative conditions.…”

Crosstalk between lysine methylation and phosphorylation of ATG16L1 dictates the apoptosis of hypoxia/reoxygenation-induced cardiomyocytes

“…Although subsequent experiments confirmed this hypothesis, we still cannot rule out the possibility that SETD7 may also methylate other proteins without harboring this consensus motif; for example, SETD7 monomethylated CTNNB1/ b-catenin and RB1 at lysine residues 180 and 810, respectively. 33,34 Moreover, we also cannot exclude the possibility that in addition to the K151 in ATG16L1, SETD7 can also methylate other sites. In fact, besides the domain of ATG16L1 that harbors K151, SETD7 also binds to amino acids 1-276.…”

Structure–Activity Relationship Studies on (R)‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7

“…This methylation mark (H3K4me) has a functional effect on the chromatin state resulting in activation of transcription. SETD7 has also been found to catalyze methylation of a range of non‐histone proteins, including estrogen receptor α (ERα), DNA methyltransferases 1 (DNMT1), TAF10, FoxO3, transcription factors YY1 and Pdx1, androgen receptor, ARTD1, β‐catenin, and tumor suppressor p53 . Recent biomedical studies revealed that SETD7 is involved in multiple signaling pathways, and its aberrant activity has been linked to various types of cancer and vascular dysfunction in patients with type 2 diabetes .…”