SMYD3通过激活SMAD2/3介导的上皮-间质转化，在肝细胞癌中诱导索拉非尼耐药。
SMYD3 induces sorafenib resistance by activating SMAD2/3-mediated epithelial-mesenchymal transition in hepatocellular carcinoma.
发表日期：2023 Jul 21
作者：
Shanshan Wang, Xin You, Xiaoshu Liu, Fengwei Zhang, Hongjuan Zhou, Xuechai Shang, Long Cai
来源：
Epigenetics & Chromatin
摘要：
药物耐药严重影响索拉非尼对肝细胞癌（HCC）的全身治疗效果。表观遗传学在药物耐药中具有重要的调控作用。然而，组蛋白甲基转移酶SET和MYND结构域含3（SMYD3）在HCC中对索拉非尼耐药的贡献仍然大部分未知。在这里，我们使用建立的索拉非尼耐药HCC细胞和异种移植模型发现SMYD3在索拉非尼耐药肿瘤和细胞中显著升高。功能上，损失和增益功能的研究表明，SMYD3促进了索拉非尼耐药HCC细胞的迁移、侵袭、转移和干细胞特性。机制上，SMYD3通过与SMAD2/3相互作用并表观遗传地促进SOX4、ZEB1、SNAIL1和MMP9基因的表达，在索拉非尼耐药HCC细胞中调控SMAD2/3介导的上皮间质转化（EMT）。总之，我们的数据证明，靶向SMYD3是克服索拉非尼耐药HCC的有效途径。© 2023作者。
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 SOX4, ZEB1, SNAIL1 and MMP9 genes. In summary, our data demonstrate that targeting SMYD3 is an effective approach to overcome sorafenib resistance in HCC.© 2023 The Author(s).