SMYD3 induces sorafenib resistance by activating SMAD2/3-mediated epithelial-mesenchymal transition in hepatocellular carcinoma
Shanshan Wang,
Xin You,
Xiaoshu Liu,
Fengwei Zhang,
Hongjuan Zhou,
Xuechai Shang,
Long Cai
Affiliations
Shanshan Wang
Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China; Corresponding author
Xin You
College of Life Science, Northeast Agricultural University, Harbin 150030, Heilong Jiang, China
Xiaoshu Liu
Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China
Fengwei Zhang
Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China
Hongjuan Zhou
Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China
Xuechai Shang
Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China
Long Cai
Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China; Corresponding author
Summary: 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.
