SMYD3: a regulator of epigenetic and signaling pathways in cancer

Abstract

Chromatin modifiers and their implications in oncogenesis have been an exciting area of cancer research. These are enzymes that modify chromatin via post-translational modifications such as methylation, acetylation, sumoylation, phosphorylation, in addition to others. Depending on the modification, chromatin modifiers can either promote or repress transcription. SET and MYN-domain containing 3 (SMYD3) is a chromatin modifier that has been implicated in the development and progression of various cancer types. It was first reported to tri-methylate Histone 3 Lysine 4 (H3K4), a methylation mark known to promote transcription. However, since this discovery, other histone (H4K5 and H4K20, for example) and non-histone (VEGFR, HER2, MAP3K2, ER, and others) substrates of SMYD3 have been described, primarily in the context of cancer. This review aims to provide a background on basic characteristics of SMYD3, such as its protein structure and tissue expression profiles, discuss reported histone and non-histone substrates of SMYD3, and underscore prognostic and functional implications of SMYD3 in cancer. Finally, we briefly discuss ongoing efforts to develop inhibitors of SMYD3 for future therapeutic use. It is our hope that this review will help synthesize existing research on SMYD3 in an effort to propel future discovery.

Keywords: Chromatin modifier; Histone methylation; Non-histone methylation; SMYD3; SMYD3 cancer implications.

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

Fig. 2

Main mechanisms of drug-mediated SMYD3 inhibition. a SMYD3 protein graphic illustrating two critical binding areas for inhibitors, the SAM- (S-adenosyl-methionine), and substrate-binding pockets. b Substrate-competitive inhibition. BCI-121 and BAY-6035 bind to the substrate-binding pocket of SMYD3. c SAM-competitive inhibition. GSK2807 binds to the SAM-binding pocket and inhibits binding of SAM to SMYD3. d Mixed-type inhibition. EPZ031686, EPZ030456, and EPZ028862 inhibit both the substrate- and SAM-binding pockets of SMYD3