Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa, Japan.
Mutagenesis. 2019 May 29;34(2):173-180. doi: 10.1093/mutage/gez002.
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.
赭曲霉毒素 A（OTA）被认为是一种人类致癌物。然而，其致癌作用的模式尚未阐明。最近，人们已经清楚地认识到，表观遗传变化会影响患癌症的风险。由于已经揭示出，由人 DNA 甲基转移酶（DNMT）转化的菌株表现出的絮凝可以通过表观遗传机制来调节，因此我们研究了 OTA 对介导絮凝表型的 FLO1 转录水平的影响。OTA 但不是致癌霉菌毒素脱氧雪腐镰刀菌烯醇（DON）以剂量依赖的方式抑制 FLO1 启动子转录调控下 GFP 荧光的强度。同时，OTA 对 CpG 基序减少的经修饰的 FLO1 启动子控制的报告基因活性没有影响。此外，还证实 OTA 降低了 DNMT 基因转化酵母（DNMT 酵母）的絮凝和 FLO1 mRNA。使用细菌 DNMT 的体外甲基化测定显示 OTA 对 DNMT 活性有抑制作用，并且 OTA 处理减少了经常在 DNMT 酵母中观察到的异常形状核的频率。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。
