Fumonisin B₁ induces global DNA hypomethylation in HepG2 cells - An alternative mechanism of action

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• 作者：Anil Chuturgoon ; Alisa Phulukdaree ; Devapregasan Moodley
• 关键词：Fumonisin B1 ; DNA hypomethylation ; Methyltransferase ; Demethylase ; Histones ; Liver cancer
• 刊名：Toxicology
• 出版年：6 January, 2014
• 年：2014
• 卷：315
• 期：Complete
• 页码：65-69
• 全文大小：1028 K

文摘

Fumonisin B₁ (FB₁), a common mycotoxin contaminant of maize, is known to inhibit sphingolipid biosynthesis and has been implicated in cancer promoting activity in animals and humans. FB₁ disrupts DNA methylation and chromatin modifications in human hepatoma (HepG2) cells. We investigated the effect of FB₁ on enzymes, DNA methyltransferases and demethylases, involved in chromatin maintenance and gross changes in structural integrity of DNA in HepG2 cells. We measured: (i) the expression of 84 key genes encoding enzymes known to modify genomic DNA and histones (superarray and qPCR); (ii) protein expression of DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) and the major demethylase (MBD2) (western blotting); (iii) degree of DNA methylation by FACS using anti-5-MeCyt and (iv) DNA migration (single cell gel electrophoresis). FB₁ significantly decreased the methyltransferase activities of DNMT1, DNMT3A and DNMT3B, and significantly up regulated the demethylases (MBD2 expression and activity, and KDM5B and KDM5C expression). FACS data showed FB₁ significantly increased DNA hypomethylation and resulted in gross changes in structural DNA as evidenced by the Comet assay. We conclude that FB₁ induces global DNA hypomethylation and histone demethylation that causes chromatin instability and may lead to liver tumourigenesis.