Ectopic expression of activation-induced cytidine deaminase caused by epigenetics modification.
Recently studies have shown that ectopic expression of activation-induced cytidine deaminase (AID) plays an important role in carcinognesis and cancer progression of inflammatory-associated cancers. Here, we examined the molecular mechanism of ectopic expression of AID in cancer cells, and whether or not nitric oxide (NO) modulates this expression, as NO is known to cause chemical deamination of the cytidine. In several cancer cell lines, treatment with the DNA methyltransferase (Dnmt) inhibitor 5-Aza-dC effected expression of AID by TNF-α, and expression was further induced by additional treatment with histone deacetylase (HDAC) inhibitors with no stimulation. The CpG sites located in the promoter and exon 1 region of the AID gene in cancer cells were found to be hypomethylated in correlation with AID expression levels. Further, administration of HDAC inhibitors also induced expression of inducible nitric oxide synthase (iNOS) in cancer cells treated with 5-Aza-dC. Interestingly, administration of S-nitroso-L-glutathione (GSNO) a nitric oxide (NO) donor, was found to enhance AID and iNOS expression in LoVo cells treated with 5-Aza-dC. Our findings suggest that AID and iNOS expression in cancer cells may be modified by epigenetic mechanisms, and that NO may further enhance AID and iNOS expression. Given recent plans to introduce Dnmt and HDAC inhibitors as novel cancer treatments, these findings regarding the potential for Dnmt and HDAC inhibitors to enhance expression of AID and iNOS, resulting in further cancer progression, might be taken into consideration.
Department of Hygiene and Preventive Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan. tatemichi@med.showa-u.ac.jp
Masayuki
M
Tatemichi
Harumi
H
Hata
Toshio
T
Nakadate
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase