PDF(Pubmed)
Abstract：
Epithelial-mesenchymal transition (EMT) refers to the transformation of polar epithelial cells into motile mesenchymal cells under specific physiological or pathological conditions, thus promoting the metastasis of cancer cells. Epithelial cadherin (E-cadherin) is a protein that plays an important role in the acquisition of tumor cell motility and serves as a key EMT epithelial marker. In the present study, AW01178, a small-molecule compound with potential therapeutic efficacy, was identified via in-cell Western high-throughput screening technology using E-cadherin as the target. The compound induced the upregulation of E-cadherin at both mRNA and protein levels and inhibited the EMT of breast cancer cells in vitro as well as metastasis in vivo. Mechanistically, AW01178 is a novel benzacetamide histone deacetylase inhibitor (HDACi) mainly targeting class I histone deacetylases. AW01178 promoted the transcription and expression of E-cadherin through enhancing the acetylation level of histone H3 in the E-cadherin promoter region, thereby inhibiting the metastasis of breast cancer cells. The collective findings support the potential utility of the novel HDACi compound identified in this study, AW01178, as a therapeutic drug for breast cancer and highlight its value for the future development of HDACi structures as anticancer drugs.
摘要：
上皮-间充质转化(EMT)是指在特定的生理或病理条件下,极性上皮细胞向活动的间充质细胞转化,从而促进癌细胞的转移。上皮钙粘蛋白(E-cadherin)是一种在肿瘤细胞运动性的获得中起重要作用的蛋白质,并且作为关键的EMT上皮标志物。在本研究中,AW01178，一种具有潜在治疗功效的小分子化合物，通过以E-cadherin为靶标的细胞内Western高通量筛选技术进行鉴定。该化合物在mRNA和蛋白质水平上诱导E-cadherin的上调，并在体外和体内抑制乳腺癌细胞的EMT。机械上,AW01178是一种新型的苯并乙酰胺组蛋白脱乙酰酶抑制剂（HDACi），主要针对I类组蛋白脱乙酰酶。AW01178通过增强E-cadherin启动子区组蛋白H3的乙酰化水平促进E-cadherin的转录和表达,从而抑制乳腺癌细胞的转移。集体发现支持了本研究中确定的新型HDACi化合物的潜在用途，AW01178，作为乳腺癌的治疗药物，突出了其未来发展HDACi结构作为抗癌药物的价值。
