DNA methylation regulates expression of VEGF-C, and S-adenosylmethionine is effective for VEGF-C methylation and for inhibiting cancer growth

Abstract

DNA hypomethylation may activate oncogene transcription, thus promoting carcinogenesis and tumor development. S-adenosylmethionine (SAM) is a methyl donor in numerous methylation reactions and acts as an inhibitor of intracellular demethylase activity, which results in hypermethylation of DNA. The main objectives of this study were to determine whether DNA hypomethylation correlated with vascular endothelial growth factor-C (VEGF-C) expression, and the effect of SAM on VEGF-C methylation and gastric cancer growth inhibition. VEGF-C expression was assayed by Western blotting and RT-qPCR in gastric cancer cells, and by immunohistochemistry in tumor xenografts. VEGF-C methylation was assayed by bisulfite DNA sequencing. The effect of SAM on cell apoptosis was assayed by flow cytometry analyses and its effect on cancer growth was assessed in nude mice. The VEGF-C promoters of MGC-803, BGC-823, and SGC-7901 gastric cancer cells, which normally express VEGF-C, were nearly unmethylated. After SAM treatment, the VEGF-C promoters in these cells were highly methylated and VEGF-C expression was downregulated. SAM also significantly inhibited tumor growth in vitro and in vivo. DNA methylation regulates expression of VEGF-C. SAM can effectively induce VEGF-C methylation, reduce the expression of VEGF-C, and inhibit tumor growth. SAM has potential as a drug therapy to silence oncogenes and block the progression of gastric cancer.

S‐Adenosylmethionine Affects ERK1/2 and Stat3 Pathways and Induces Apotosis in Osteosarcoma Cells

“…AdoMet has been shown to reverse DNA hypomethylation of promoters of oncogenes such as c-myc and H-ras, thus downregulating their expression in human gastric cancer and colon cancer (Luo et al, 2010). Moreover, it has been found that AdoMet is able to effectively induce VEGF-C methylation and downregulate VEGF-C expression in gastric cells and to significantly inhibit tumor growth in vitro and in vivo (Da et al, 2014). In addition, it has been reported that AdoMet can inhibit beta catenin, the main effector of Wnt signaling, as well as other oncogenic mechanisms like AKT to promote apoptosis and attenuate growth progression in liver and colon cancers Li et al, 2015).…”

miR-148a-3p inhibits DNMT1-mediated methylation of VEGF and promotes proliferation and invasion in glioma cells via the PI3K/Akt/eNOS signaling pathway

“…The growth and metastasis of cancer cells depend on angiogenesis. The vascular endothelial growth factor is the most potent pro-angiogenic factor [15,22]. It is involved in the regulation of cell proliferation, survival and invasiveness [14].…”

“…Silencing VEGF has inhibited cell proliferation and angiogenesis in human osteosarcoma [13] and also suppressed the occurrence of lung cancer [14]. Other evidence suggests that the expression of VEGF is regulated by its methylation, hypermethylation of VEGF caused a decrease in the expression of mRNA [15,16]. In atherosclerotic, folic acid reduced atherosclerotic lesion through elevating DNA methyltransferase activity and expression, altering MCP1 and VEGF promoter methylation, and inhibiting MCP1 and VEGF expression [17].…”

GADD45β induction by S-adenosylmethionine inhibits hepatocellular carcinoma cell proliferation during acute ischemia-hypoxia

“…Most patients with liver injury or a chronic liver disease, like cirrhosis, have impaired SAMe biosynthesis due to reduced MAT1A expression and MAT I/III inactivation, which are respectively the enzyme and isoenzyme involved in SAMe synthesis in normal hepatocytes [11, 12]. SAMe may inhibit tumor growth, reduce tumor invasiveness and slow metastasis through methyl group donation leading to gene hypermethylation and reduction of overall hypomethylation to inhibit oncogene expression [13–15]. …”