SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth

Abstract

SMYD2 is a histone methyltransferase, which methylates both histone H3K4 as well as a number of non-histone proteins. Dysregulation of SMYD2 has been associated with several diseases including cancer. In the present study, we investigated whether and how SMYD2 might contribute to colorectal cancer. Increased expression levels of SMYD2 were detected in human and murine colon tumor tissues compared to tumor-free tissues. SMYD2 deficiency in colonic tumor cells strongly decreased tumor growth in two independent experimental cancer models. On a molecular level, SMYD2 deficiency sensitized colonic tumor cells to TNF-induced apoptosis and necroptosis without affecting cell proliferation. Moreover, we found that SMYD2 targeted RIPK1 and inhibited the phosphorylation of RIPK1. Finally, in a translational approach, pharmacological inhibition of SMYD2 attenuated colonic tumor growth. Collectively, our data show that SMYD2 is crucial for colon tumor growth and inhibits TNF-induced apoptosis and necroptosis.

SET and MYND domain-containing protein 2 (SMYD2): A prognostic biomarker associated with immune infiltrates in cervical squamous cell carcinoma and endocervical adenocarcinoma

“…The protein lysine methyltransferase SMYD2 functions as an oncogene involved in regulating its downstream target genes through histone or non-histone methylation and suppression of p53 activity to promote the metabolism of glucose [13,17]. These factors may influence tumor-cell proliferation, apoptosis, metastasis and chemosensitivity [14,18]. In this research, SMYD2 knockdown inhibited the growth of CaSki and SiHa cells, which indicated that SMYD2 acts as a tumor "instigator" in CESC.…”

A lymph node-to-tumour PDL1+macrophage circuit antagonizes dendritic cell immunotherapy

“…Fig. S11A-B), as reported previously (Yu et al, 2022). We therefore focused on apoptotic MC38 DCvax-IT.…”

SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells

“…In the context of a project aimed to study the role of SMYD2 in cancer [36], SMYD2sufficient and SMYD2-deficient HT-29 cells (Figure 1A), a human colorectal cancer cell line that has been widely used for many years, were implanted into Rag1 −/− mice via subcutaneous injection, and RNA-seq analysis of HT-29 xenografts was performed (Figure 1B). Interestingly, RNA-seq data analyses revealed that transcript levels of TMPRSS2 were significantly lower in both clones of SMYD2-deficient cells as compared to WT cells (Figure 1C).…”

“…HT-29 (ATCC ® HTB-38™) cells were maintained in DMEM supplemented with 10% FCS and 1% penicillin/streptomycin (P433, Sigma-Aldrich, St. Louis, MO, USA). SMYD2 knockout cell lines were established as previously described [36]. Caco-2 cells (kindly provided by Konstantin Sparrer, University Hospital Ulm, Germany) were cultivated in DMEM, additionally containing 1× MEM Non-Essential Amino Acids Solution (11140050, Thermo Fisher Scientific).…”