Fig. 1

Selected mechanisms of action of SMYD3 as an oncogenic driver. a Histone-mediated mechanisms. (i) SMYD3 tri-methylates H3K4, with HSP90A enhancing its enzymatic activity. (ii) SMYD3 tri-methylates H4K20. In ovarian cancer cells, CDKN2A is repressed via SMYD3-mediated H4K20 tri-methylation. b Non-Histone-mediated mechanisms. (i) SMYD3 methylates vascular endothelial growth factor receptor 1 (VEGFR1) at lysine 831 and enhances its kinase activity. (ii) SMYD3 methylates mitogen-activated protein kinase kinase kinase 2 (MAP3K2) at lysine 260, preventing its dephosphorylation by protein phosphatase 2 (PP2A) and activating the MAP kinase pathway. (iii) SMYD3 methylates v-Akt murine thymoma viral oncogene homolog 1 (AKT1) at lysine 14 and increases its phosphorylation and activation. (iv) SMYD3 acts as a co-activator of the estrogen receptor (ER), increasing the transcription of ER-mediated downstream genes. (v) SMYD3 methylates human epidermal growth factor receptor 2 (HER2) at lysine 175, enhancing HER2 homodimerization and autophosphorylation