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.
Highlights
Colorectal cancer (CRC) is one of the leading causes of cancerdeaths worldwide and is expected to increase by 60% by the year 2030 [1, 2]
Apoptosis is a form of programmed cell death and its inhibition plays an important role in CRC tumor development [15, 16]
Progressive inhibition of apoptosis is associated with the transformation of colorectal epithelial to carcinoma cells and decreased apoptosis has been observed in CRC tissues [17, 18]
Summary
Colorectal cancer (CRC) is one of the leading causes of cancerdeaths worldwide and is expected to increase by 60% by the year 2030 [1, 2]. Using MC-38 and HT-29 cells, we demonstrated that SMYD2 is dispensable for cell proliferation but crucial for inhibiting TNF-induced apoptosis and necroptosis. We identified SMYD2 as an important molecule for colon tumor growth via regulating TNF-induced apoptosis and necroptosis.
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