SMYD3通过激活SMAD2/3介导的肝细胞癌上皮-间质转化诱导索拉非尼耐药。

SMYD3 induces sorafenib resistance by activating SMAD2/3-mediated epithelial-mesenchymal transition in hepatocellular carcinoma.

作者信息

Wang Shanshan, You Xin, Liu Xiaoshu, Zhou Hongjuan, Shang Xuechai, Cai Long

机构信息

Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China.

College of Life Science, Northeast Agricultural University, Harbin 150030, Heilong Jiang, China.

出版信息

iScience. 2023 May 29;26(7):106994. doi: 10.1016/j.isci.2023.106994. eCollection 2023 Jul 21.

Drug resistance prominently hampers the effects of systemic therapy of sorafenib to hepatocellular carcinoma (HCC). Epigenetics have critical regulatory roles in drug resistance. However, the contributions of histone methylatransferase SET and MYND domain containing 3 (SMYD3) to sorafenib resistance in HCC remain largely unknown. Here, using our established sorafenib-resistant HCC cell and xenograft models, we found SMYD3 was markedly elevated in sorafenib-resistant tumors and cells. Functionally, loss- and gain-of-function studies showed that SMYD3 promoted the migration, invasion, metastasis and stemness of sorafenib-resistant HCC cells. Mechanistically, SMYD3 is required for SMAD2/3-mediated epithelial-mesenchymal transition (EMT) in sorafenib-resistant HCC cells by interacting with SMAD2/3 and epigenetically promoting the expression of and genes. In summary, our data demonstrate that targeting SMYD3 is an effective approach to overcome sorafenib resistance in HCC.

耐药性显著阻碍了索拉非尼对肝细胞癌（HCC）全身治疗的效果。表观遗传学在耐药性中具有关键的调控作用。然而，组蛋白甲基转移酶SET和含MYND结构域蛋白3（SMYD3）对HCC中索拉非尼耐药性的作用在很大程度上仍不清楚。在此，利用我们建立的索拉非尼耐药HCC细胞和异种移植模型，我们发现SMYD3在索拉非尼耐药肿瘤和细胞中显著升高。在功能上，功能缺失和功能获得研究表明，SMYD3促进了索拉非尼耐药HCC细胞的迁移、侵袭、转移和干性。从机制上讲，SMYD3通过与SMAD2/3相互作用并在表观遗传上促进和基因的表达，从而在索拉非尼耐药HCC细胞中参与SMAD2/3介导的上皮-间质转化（EMT）过程。总之，我们的数据表明，靶向SMYD3是克服HCC中索拉非尼耐药性的有效方法。