Oroxylin A inhibits the migration of hepatocellular carcinoma cells by inducing NAG-1 expression
Oroxylin A inhibits the migration of hepatocellular carcinoma cells by inducing NAG-1 expression
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Oroxylin A 通过诱导 NAG-1 表达抑制肝癌细胞迁移
DOI：
10.1038/s41401-021-00695-4
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发表时间：
2021
影响因子：
8.2
通讯作者：
Qiang Lei
中科院分区：
文献类型：
--
作者：
Huo Tongxin;Wang Xiaoping;Yu Zhou;Kong Bo;He Yuan;Guo Qinglong;Zhang Xiaobo;Qiang Lei
肝细胞癌（Hepatocellular carcinoma，HCC）是最常见的肝癌，由于其肝内和远处转移，被认为是最致命的恶性肿瘤之一。在本研究中，我们证明了从紫藤中提取的天然产物oroxylin A显著抑制转化生长因子-β 1（TGF-β1）诱导的肝癌上皮-间质转化（EMT）和转移。Oroxylin A通过上调非甾体抗炎药激活基因-1（NAG-1）表达阻断TGF-β1/Smad信号通路。Oroxylin A通过调节CCAAT/增强子结合蛋白β（C/EBPβ）的乙酰化来促进NAG-1的转录，CCAAT/EBPβ是一种与NAG-1启动子结合的转录因子。其作用机制可能是通过与GLY 149残基形成氢键，与组蛋白脱乙酰酶1（HDAC 1）相互作用，诱导蛋白酶体降解HDAC 1，进而抑制HDAC 1介导的C/EBPβ的脱乙酰化，促进NAG-1的表达。总之，我们的研究结果揭示了一个以前未知的肿瘤抑制机制的oroxylin A。Oroxylin A作为一种潜在的抑制肝癌转移的候选药物值得进一步研究。
Hepatocellular carcinoma (HCC), the most prevalent liver cancer, is considered one of the most lethal malignancies with a dismal outcome mainly due to frequent intrahepatic and distant metastasis. In the present study, we demonstrated that oroxylin A, a natural product extracted fromScutellaria radix, significantly inhibits transforming growth factor-beta1 (TGF-β1)-induced epithelial–mesenchymal transition (EMT) and metastasis in HCC. Oroxylin A blocked the TGF-β1/Smad signaling via upregulating the non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) expression. Oroxylin A promoted NAG-1 transcription by regulating the acetylation of CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor that binds to the NAG-1 promoter. In terms of the underlying mechanism, oroxylin A may interact with histone deacetylase 1 (HDAC1) by forming hydrogen bonds with GLY149 residue and induce proteasome-mediated degradation of HDAC1 subsequently impairing HDAC1-mediated deacetylation of C/EBPβ and promoting the expression of NAG-1. Taken together, our findings revealed a previously unknown tumor-suppressive mechanism of oroxylin A. Oroxylin A should be further investigated as a potential clinical candidate for inhibiting HCC metastasis.