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

Drug resistance prominently hampers the effects of systemic therapy of sorafe-nib 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-resis-tant tumors and cells. Functionally, loss-and gain-of-function studies showed that SMYD3 promoted the migration, invasion, metastasis and stemness of sora-fenib-resistant HCC cells. Mechanistically, SMYD3 is required for SMAD2/3-medi-ated 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 target-ing SMYD3 is an effective approach to overcome sorafenib resistance in HCC.