Overexpression of histone methyltransferases SUV39H1 and SUV39H2 in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although the underlying molecular mechanisms remain elusive, accumulating evidence has revealed that aberrant epigenetic events, such as promoter DNA methylation, play a crucial role in liver carcinogenesis. DNA methylation and histone modifications work very closely in regulating proper chromatin structure and gene expression. However, the role of aberrant histone methylation in HCC has not been fully characterized thus far. Methylation on lysine 9 residue of histone 3 protein is an important epigenetic mark for transcriptional repression and heterochromatin formation. In human, H3K9 methylation is catalyzed by SUV39H1 and SUV39H2, human orthologs of Drosophila transcriptional repressor Su(Var)3-9. In this study, using real-time quantitative RT-PCR, we found that both SUV39H1 and SUV39H2 were frequently overexpressed in primary HCC when compared with their corresponding non-tumorous livers. SUV39H1 and SUV39H2 overexpression was found in 60% and 63% of primary HCC, respectively. Clinicopathologically, overexpression of SUV39H1 and SUV39H2 were both significantly associated with the presence of HCC venous invasion (P = 0.020 and 0.043, respectively), an indicator of HCC metastasis. Consistently, ectopic overexpression of SUV39H1 promoted cell migration and invasion of immortalized liver cell line, suggesting that overexpression of SUV39H1/2 may contribute to HCC metastasis. Furthermore, treatment of Su(Var)3-9 inhibitor, Chaetocin, induced G2/M arrest and apoptosis, and suppressed the growth of HCC cell lines at very low concentrations (at nM levels). Our findings suggest that the overexpression of the SUV39H1 and SUV39H2 may play an important role in human HCC and may be potential targets for epigenetic therapy.