SMYD3 promotes epithelial ovarian cancer metastasis by downregulating p53 protein stability and promoting p53 ubiquitination.

Epithelial ovarian cancer (EOC) has a very poor prognosis because of tumor invasiveness. Here, we reported that SET and MYND domain containing protein 3 (SMYD3), a lysine methyltransferase, was frequently upregulated in EOC and associated with poor prognosis. A series of in vitro assays demonstrated that SMYD3 significantly upgraded the migration ability of EOC cells. The results of in vivo EOC metastasis models further confirmed that overexpression of SMYD3 promoted EOC progression. Mechanistic investigations indicated that SMYD3 cloud decrease p53 protein stability and induce epithelial-mesenchymal transition in EOC cells. SMYD3 interacts with p53 directly via the post-SET domain and destabilizes p53 by inducing p53 translocation from the nucleus to the cytoplasm and promoting p53 ubiquitination modification independent of MDM2. Furthermore, the mass spectrometry results showed that SMYD3 interacts with UBE2R2, an ubiquitin-conjugating enzyme (E2) of the ubiquitin-proteasome pathway. The combination of UBE2R2-SMYD3-p53 significantly promotes the ubiquitination and degradation of p53. These results pointed that SMYD3 might be a new E3 ligase of p53. Further analysis confirmed that lysines 381, 382 and 386 of p53 are the key sites for the ubiquitination modification of SMYD3 to p53. In summary, our results define the important role of SMYD3 in the metastasis process of EOC and present a new therapeutic target against EOC.