Therapeutic Effect On HCC Of Targeted Inhibition Of SMYD3 Gene By RNA Interference

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related with death worldwide. Lately, the regulation of gene expression by post-translational modifications of histones was shown to be involved in the development of various cancers including HCC. SET- and MYND- domain containing protein 3 (SMYD3), encoding a protein which contains SET domain and has histone H3-lysine 4-specific (H3-K4) methyltransferase (HMTase) activity, was regarded as one important histone modification enzyme. Tumor Suppressor Genes (TSGs) inactivation were involved in carcinogenesis and progress. Retinoblastoma protein-interacting zinc finger gene (RIZ1), one typical TSG with H3-K9 methyl transferase activity, was found to be hypermethylated and down-regulated in various tumors. To clarify the role of SMYD3 in HCC development and progress and if its regulation activity was through RIZ1 inactivation, expression of SMYD3 in hepatoma cell lines including HepG2, Hep3B, and SMMC-7721 were measured; Knockdown of SMYD3 expression in HepG2 cell with RNA interference (RNAi) and hepatoma cell proliferation, migration and apoptosis were tested, with RIZ1 CpG promoter methylation and corresponding mRNA expression were investigated. We found that, SMYD3 was over-expressed in HCC, with RIZ1 hypermethylation and mRNA down-expression. Suppression of SMYD3 expression de-methylated RIZ1 CpG promoter and increased RIZ1 mRNA expression. Consequently, SMYD3 down-expression with RIZ1 de-methylation strongly inhibited hepatoma cell growth and migration, induced apoptosis in HepG2. In conclusion, these results demonstrate that SMYD3 plays a critical role in the development and progress of hepatocellular carcinoma, the proliferation, migration induction and apoptosis inhibition activity of SMYD3 may be through RIZ1 CpG promoter hypermethylation.