DNA methylation regulates expression of VEGF-C, and S-adenosylmethionine is effective for VEGF-C methylation and for inhibiting cancer growth.
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.
Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, China.
M X
MX
Da
Department of Surgery, Ningxia Medical University, Yinchuan, China.
Y B
YB
Zhang
Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, China.
J B
JB
Yao
Department of Surgery, Ningxia Medical University, Yinchuan, China.
Y X
YX
Duan
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008819:Mice, Nude; D009857:Oncogenes / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D042582:Vascular Endothelial Growth Factor C; D012436:S-Adenosylmethionine