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.

中文翻译：

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曲霉毒素A对DNMT介导的酵母絮凝的抑制作用。

霉菌毒素曲霉毒素A（OTA）被认为是人类致癌物。然而，其致癌作用的方式尚未阐明。近来，已经明显的是，表观遗传学变化会影响患癌症的风险。由于已经发现由人DNA甲基转移酶（DNMT）转化的菌株所显示的酵母絮凝作用可以通过表观遗传机制进行调控，因此我们研究了OTA对FLO1转录水平的影响，FLO1介导了絮凝表型。在FLO1启动子的转录调控下，OTA而非非致癌性真菌毒素脱氧雪腐酚（DON）抑制GFP荧光强度。同时，在具有降低的CpG基序的修饰的FLO1启动子的控制下，OTA对报道分子的活性没有影响。此外，证实了通过OTA减少了DNMT基因转化酵母（DNMT酵母）的絮凝和FLO1 mRNA。使用细菌DNMT进行的体外甲基化分析显示，OTA对DNMT活性具有抑制作用，并且OTA处理降低了DNMT酵母中经常观察到的异形核的频率。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。