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

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

  • iScience. 2023 May 29;26(7):106994. doi: 10.1016/j.isci.2023.106994.
Shanshan Wang 1,  Xin You 2,  Xiaoshu Liu 1,  Fengwei Zhang 1,  Hongjuan Zhou 1,  Xuechai Shang 1,  Long Cai 1
Affiliations

Affiliations

  • 1 Central Laboratory, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, 208 Huancheng Dong Road, Hangzhou 310003, Zhejiang, China.
  • 2 College of Life Science, Northeast Agricultural University, Harbin 150030, Heilong Jiang, China.
PMID: 37534166 DOI: 10.1016/j.isci.2023.106994
Abstract

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.

Keywords

Cancer; Drugs; Epigenetics.

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