SMYD3
SMYD3 activity is linked to the immune system in many ways, including macrophage function, T cells and blood malignancies. In regard to macrophages, Yıldırım-Buharalıoglu et al. observed that 18 hours after interferon gamma (IFNγ) treatment of colony-stimulating factor 1 (CSF1)-differentiated primary human macrophages, SMYD3 mRNA levels decreased, in parallel with a reduction in cell proliferation (Yildirim-Buharalioğlu et al. 2017). Furthermore, under hyperglycaemic conditions, SMYD3, together with SET7/9, activated S100 calcium binding protein A12 (S100A12) expression by methylation of theS100A12 promoter in classically activated M1 macrophages (Mossel et al. 2020).
SMYD3 plays a role in host immunity in relation to the human T-cell lymphotropic virus type 1 (HTLV-1, also known as human T-cell leukaemia type 1). This virus is linked to leukemogenesis, among other pathological processes. Yamamoto et al. revealed that there is endogenous SMYD3 expression in T cell lines and primary T cells, in which it directly interacts with HTLV-1 Tax and supports its cytoplasmic localisation. By controlling Tax subcellular localization, SMYD3 permits or hampers its interaction with cytoplasmic or nuclear proteins (Yamamoto et al. 2011). Additionally, Nagata et al. claimed that SMYD3 is involved in the epigenetic regulation of inducible regulatory T (iTreg) cells. SMYD3 catalysed histone 3 lysine 4 (H3K4) trimethylation in the promoter region and conserved the noncoding DNA sequence of thefoxp3 gene and regulated its expression in a transforming growth factor-beta1 / mothers against decapentaplegic homolog 3 (TGFβ1/Smad3)-dependent manner. Hence, inhibition of SMYD3 impaired iTreg cell formation. Accordingly, SMYD3 KO mice infected with the respiratory syncytial virus displayed exaggerated inflammatory responses and aggravation of the disease, due to the key role of iTreg in this viral infection (Nagata et al. 2015).
Regarding blood cancers, SMYD3 plays a role in all three principal types: leukaemia, lymphoma and myeloma. Liu et al. described a mechanism by which SMYD3 participates in the development of Hodgkin lymphoma via H3K4 methylation at the promoter of 15-Lipoxygenase-1 (15-LOX-1). Deregulation of this protein is observed in many cancer and pathological immunological conditions, including lymphoma (Liu et al. 2012). SMYD3 is upregulated by signal transducer and activator of transcription 3 (STAT3) in chronic lymphocytic leukaemia. The STAT3-SMYD3 axis promotes carcinogenesis, since high SMYD3 levels show a negative correlation with suppression of cell proliferation and invasion capacity. Downregulation of the phosphorylation of STAT3 by means of the STAT3 inhibitor WP1066 suppressed STAT3 binding to the SMYD3promoter, consequently inhibiting SMYD3 gene expression (Ma et al. 2019; F. Lin et al. 2019). Ectopic overexpression of SMYD3 in a human leukaemia cell line induced mRNA expression of the c-Met oncogen, thereby providing a rationale to test SMYD3 inhibitors for the treatment of leukaemia (Zou et al. 2009).
Moreover, knockdown of SMYD3 caused mRNA and protein levels upregulation of C-X-C motif chemokine ligand 9 (CXCL9), C-X-C motif chemokine ligand 10 (CXCL10), C-X-C motif chemokine ligand 11 (CXCL11) and transporter 1, ATP binding cassette subfamily B member (TAP1) in human papilloma virus-negative squamous cell carcinoma of the head and neck cell lines, suggesting a role of SMYD3 in cytokine release (Vougiouklakis et al. 2017).
Natural compounds can affect SMYD3 expression in cancer. Zhaoet al. attempted to elucidate the anti-tumoural mechanism of action of triptolide (the main active component of extracts from the Chinese herb Tripterygium wilfordii Hook.F) in a human multiple myeloma cell line and found that triptolide downregulates SMYD3(Zhao et al. 2010). Furthermore, the isoquinoline plant alkaloid berberine also downregulated SMYD3 gene expression in the same cell line (Z. Wang et al. 2016).