Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression

Abstract

We identified SMYD2, a SMYD (SET and MYND domain) family protein with lysine methyltransferase activity, as a novel breast cancer oncogene. SMYD2 was expressed at significantly higher levels in breast cancer cell lines and in breast tumor tissues. Silencing of SMYD2 by RNAi in triple-negative breast cancer (TNBC) cell lines or inhibition of SMYD2 with its specific inhibitor, AZ505, significantly reduced tumor growth in vivo. SMYD2 executes this activity via methylation and activation of its novel non-histone substrates, including STAT3 and the p65 subunit of NF-κB, leading to increased TNBC cell proliferation and survival. There are cross-talk and synergistic effects among SMYD2, STAT3, and NF-κB in TNBC cells, in that STAT3 can contribute to the modification of NF-κB p65 subunit post-translationally by recruitment of SMYD2, whereas the p65 subunit of NF-κB can also contribute to the modification of STAT3 post-translationally by recruitment of SMYD2, leading to methylation and activation of STAT3 and p65 in these cells. The expression of SMYD2 can be upregulated by IL-6-STAT3 and TNFα-NF-κB signaling, which integrates epigenetic regulation to inflammation in TNBC development. In addition, we have identified a novel SMYD2 transcriptional target gene, PTPN13, which links SMYD2 to other known breast cancer associated signaling pathways, including ERK, mTOR, and Akt signaling via PTPN13 mediated phosphorylation.

The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells

“…SMYD2, which belongs to the group of transcriptional regulators containing SET and MYND domains, is responsible for complex transcriptional regulation through histone methylation and non-histone protein methylation (24,25). Previous studies have suggested that SMYD2 is upregulated in several types of cancer, including pediatric acute lymphoblastic leukemia, gastric cancer and breast cancer (26)(27)(28). Additionally, previous studies have highlighted the role of SMYD2 in the regulation of cancer cell growth (13,17).…”

Role of STAT3 signaling pathway in breast cancer

“…Li et al have found that histone deacetylase 6 (HDAC6), a class II histone deacetylase, and prostaglandin E2 and COX2, can upregulate STAT3 activation in breast cancer [18]. In addition, lysine methyltransferase SMYD2 can activate the methylation and phosphorylation of STAT3 to promote breast cancer progression [19]. MicroRNA (miR) has become a hot topic in the fields of cancer biology and development in recent years.…”

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

“…The cells were scraped using sterilized 10 μL pipette tips and washed with 0.1% serum media and stimulated with PDGF‐BB (20 ng·mL −1 ) (Du et al, ). For the signalling pathway study, the following chemical inhibitors were used: S3I‐201 (100 μM) (Li et al, ), U0126 (1 μM) (Pathria et al, ), LY294002 (30 μM) (Liao et al, ), staurosporine (50 nM) (Prins et al, ) and 3‐TYP (20 nM) (Shumin et al, ). All these inhibitors were purchased from Selleck Chemicals (Houston, TX, USA).…”