Silencing SMYD3 in hepatoma demethylates RIZI promoter induces apoptosis and inhibits cell proliferation and migration

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Abstract
To investigate the role of SMYD3 in hepatocellular carcinoma (HCC) development and progression and to verify whether its regulation activity was through RIZ1 inactivation. Expression of SMYD3 in HCC cell lines and tissues were measured; silencing of SMYD3 by RNA interference (RNAi) was effectuated, hepatoma cell proliferation, migration and apoptosis were tested, with RIZ1 CpG promoter methylation, and corresponding mRNA expression were investigated. SMYD3 over-expression in HCC was associated with RIZ1 hypermethylation and mRNA down-expression. Suppression of SMYD3 expression de-methylated RIZ1 CpG promoter (P < 0.01) and increased RIZ1 mRNA expression (P < 0.01). Consequently, SMYD3 down-expression with RIZ1 de-methylation strongly inhibited hepatoma cell growth (MTT inhibitory rates: Pgenesil-1-s1 60.95% +/- 7.97%, Pgenesil-1-s2 72.14% +/- 9.68% vs Pgenesil-1-hk 6.89% +/- 4.12%, P < 0.01) and migration (Pgenesil-1-s1 4.24% +/- 1.58%, Pgenesil-1-s1 4.87% +/- 0.73% vs Pgenesil-1 19.03% +/- 4.63%, Pgenesil-1-hk 19.95% +/- 5.21%, P < 0.01) and induced apoptosis (FCM subG1 phase Pgenesil-1-s1 19.07% +/- 1.78%, Pgenesil-1-s2 17.68% +/- 2.36% vs Pgenesil-1 0.47% +/- 0.12%, Pgenesil-1-hk 1.46% +/- 0.28%, P < 0.01. TUNEL-positive cells: Pgenesil-1-s1 40.24% +/- 5.18%, Pgenesil-1-s2 38.48% +/- 4.65% vs Pgenesil-1 2.18% +/- 1.34%, Pgenesil-1-hk 2.84% +/- 1.22%, P < 0.01) in HepG2 cells. These results demonstrate that SMYD3 plays a critical role in the carcinogenesis and progression of HCC. The proliferation, migration induction and apoptosis inhibition activities of SMYD3 may be mediated through RIZ1 CpG promoter hypermethylation.

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