Department of Pharmacology and Toxicology, University of Louisville Health Science Center, Louisville, KY 40202, USA; University of Louisville Alcohol Research Center, Louisville, KY 40202, USA.
Department of Pharmacology and Toxicology, University of Louisville Health Science Center, Louisville, KY 40202, USA; University of Louisville Alcohol Research Center, Louisville, KY 40202, USA.
Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2586-2594. doi: 10.1016/j.bbadis.2019.07.002. Epub 2019 Jul 8.
Ethanol-induced apoptosis in neural crest cells (NCCs), a multipotent progenitor cell population, is implicated in the Fetal Alcohol Spectrum Disorders (FASD). Studies have demonstrated that sulforaphane (SFN) can prevent ethanol-induced apoptosis in NCCs. The objective of this study is to investigate whether ethanol exposure can induce apoptosis in NCCs by inhibiting epithelial-mesenchymal transition (EMT) and whether SFN can prevent ethanol-induced apoptosis by epigenetically modulating the expression of Snail1, a key transcriptional factor that promotes EMT. We found that ethanol exposure resulted in a significant increase in apoptosis in NCCs. Co-treatment with SFN significantly reduced ethanol-induced apoptosis. Treatment with SFN also dramatically diminished ethanol-induced changes in the expression of E-cadherin and vimentin, and restored EMT in ethanol-exposed NCCs. In addition, ethanol exposure reduced the levels of trimethylation of histone H3 lysine 4 (H3K4me3) at the promoters of Snail1. SFN treatment diminished the ethanol-induced reduction of H3K4me3 at the promoter regions of the Snail1 gene, restored the expression of Snail1 and down-regulated Snail1 target gene E-cadherin. Knockdown of Snail1 significantly reduced the protective effects of SFN on ethanol-induced apoptosis. These results demonstrate that SFN can protect against ethanol-induced apoptosis by preventing ethanol-induced reduction in the levels of H3K4me3 at the promoters of Snail1, restoring the expression of Snail1 and EMT in ethanol-exposed NCCs.
乙醇诱导神经嵴细胞（NCCs）凋亡，NCCs 是一种多能祖细胞群体，与胎儿酒精谱系障碍（FASD）有关。研究表明，萝卜硫素（SFN）可以预防 NCCs 中的乙醇诱导凋亡。本研究旨在探讨乙醇暴露是否可以通过抑制上皮-间充质转化（EMT）诱导 NCCs 凋亡，以及 SFN 是否可以通过表观遗传调节 EMT 促进转录因子 Snail1 的表达来预防乙醇诱导的凋亡。我们发现，乙醇暴露会导致 NCCs 凋亡显著增加。SFN 共处理可显著减少乙醇诱导的凋亡。SFN 处理还显著降低了乙醇诱导的 E-钙粘蛋白和波形蛋白表达变化，并恢复了乙醇暴露的 NCCs 中的 EMT。此外，乙醇暴露降低了 Snail1 基因启动子上组蛋白 H3 赖氨酸 4（H3K4me3）的三甲基化水平。SFN 处理减少了乙醇诱导的 Snail1 基因启动子区域 H3K4me3 的减少，恢复了 Snail1 的表达并下调了 Snail1 靶基因 E-钙粘蛋白。Snail1 的敲低显著降低了 SFN 对乙醇诱导凋亡的保护作用。这些结果表明，SFN 可以通过防止乙醇诱导的 Snail1 基因启动子区域 H3K4me3 水平降低，恢复乙醇暴露的 NCCs 中 Snail1 的表达和 EMT，从而预防乙醇诱导的凋亡。
