Inhibitory effect of ochratoxin A on DNMT-mediated flocculation of yeast
Inhibitory effect of ochratoxin A on DNMT-mediated flocculation of yeast
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DOI：
10.1093/mutage/gez002
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发表时间：
2019-03-01
期刊：
影响因子：
2.7
通讯作者：
Honma, Masamitsu
中科院分区：
文献类型：
--
作者：
Sugiyama, Kei-ichi;Furusawa, Hiroko;Honma, Masamitsu
真菌毒素赭曲霉毒素A（OTA）被认为是一种人类致癌物质。然而，其致癌作用的模式尚未阐明。最近，表观遗传变化影响癌症发生的风险已经变得很明显。由于它已被揭示，酵母絮凝显示的菌株转化与人类DNA甲基转移酶（DNMT）可以调节表观遗传机制，我们研究了OTA的转录水平上的FLO1，它介导的絮凝表型的影响。OTA而非致癌性真菌毒素脱氧雪腐镰刀菌烯醇（DON）以剂量依赖方式抑制FLO1启动子转录调控下的GFP荧光强度。同时，OTA对修饰后的FLO1启动子的报告活性没有影响。此外，证实了OTA降低了DNMT基因转化酵母（DNMT酵母）的絮凝性和FLO1 mRNA。使用细菌DNMT的体外甲基化测定揭示了OTA对DNMT活性的抑制作用，并且OTA处理降低了DNMT酵母中经常观察到的异常形状的核的频率。这些结果表明，OTA的致癌性可能涉及抑制DNMT介导的表观遗传调控。
The mycotoxin ochratoxin A (OTA) is considered to be a human carcinogen. However, the mode of its carcinogenetic action has not been elucidated. Recently, it has become evident that epigenetic changes influence the risk of developing cancer. Since it has been revealed that the yeast flocculation displayed by the strains transformed with human DNA methyltransferases (DNMT) can be regulated by epigenetic mechanisms, we examined the effect of OTA on the transcription level of FLO1, which mediates the flocculation phenotype. OTA but not a non-carcinogenetic mycotoxin deoxynivalenol (DON) inhibited the intensity of GFP fluorescence under the transcriptional regulation of FLO1 promoter in a dose-dependent manner. At the same time, OTA had no effect on the reporter activity under the control of modified FLO1 promoter with reduced CpG motifs. In addition, it was confirmed that the flocculation and FLO1 mRNA of DNMT gene-transformed yeast (DNMT yeast) were decreased by OTA. In vitro methylation assay using a bacterial DNMT revealed an inhibitory effect of OTA on the DNMT activity, and OTA treatment reduced the frequency of abnormally shaped nuclei which were often observed in DNMT yeast. These results suggest that the carcinogenicity of OTA may involve inhibition of DNMT-mediated epigenetic regulation.