Abstract 1059: SUV39H1 promotes HCC tumorigenesis and is targeted by tumor suppressive miRNA-125b

Abstract

Abstract Epigenetic alternation is a common dysregulated event in hepatocellular carcinoma (HCC) development. Through interrogating the expression of 90 major epigenetic regulating genes, we identified SUV39H1, the prototype histone methyltransferase as one of the most frequently up-regulated epigenetic regulators in human HCC (61%, 23/38). SUV39H1 is responsible for H3K9 trimethylation establishment and essentially involves in heterochromatin formation and transcriptional repression. We found that SUV39H1 up-regulation in human HCC was significantly associated with increased Ki67 expression (P < 0.001) and the presence of venous invasion (P = 0.020), suggesting the importance of SUV39H1 in HCC tumor growth and metastasis. To investigate the functions of SUV39H1 in human HCC, both gain- and loss-of-function models were established. Ectopic expression of SUV39H1 remarkably enhanced cell clonogenicity and migratory ability of immortalized hepatocytes. Conversely, stable knockdown of SUV39H1 by shRNA substantially reduced cell proliferation, colony formation and migration of HCC cells. In addition, an elevated lysosomal β-galactosidase activity in SUV39H1 knockdown cells was observed and suggested the senescence-suppressive role of SUV39H1 in cancer progression. Consistent with previous observations, treatment of SUV39H1 inhibitor (Chaetocin) drastically suppressed cell proliferation and induced apoptosis in HCC cells. The oncogenic function of SUV39H1 was further demonstrated by in vivo experiments, knockdown of SUV39H1 significantly inhibited tumorigenicity of HCC cells in both subcutaneous and orthotopic mouse model. Most importantly, SUV39H1 knockdown abolished pulmonary metastasis of HCC cells in orthotopic tumor implantation model. To further investigate the underlying mechanism of SUV39H1 up-regulation in HCC, we explored the potential regulation of SUV39H1 by microRNA. In silico analysis suggested SUV39H1 as a putative target of miR-125b. Ectopic expression of miR-125b precursor in HCC cells significantly inhibited SUV39H1 3′UTR luciferase reporter activity and suppressed endogenous SUV39H1 expression at both mRNA and protein levels. Interestingly, down-regulation of miR-125b was frequently observed in human HCC (70%, 38/54) and was inversely correlated with SUV39H1 expression (P = 0.001). Taken together, we demonstrated that SUV39H1 was frequently up-regulated in human HCC and functioned as an oncogene in promoting HCC progression and metastasis. miR-125b negatively regulated SUV39H1 expression and downregulation of miR-125b may account for SUV39H1 up-regulation in human HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1059. doi:1538-7445.AM2012-1059