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Article first published online: 6 DEC 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 637–647, February 2013
How to Cite
Ngo-Yin Fan, D., Ho-Ching Tsang, F., Hoi-Kam Tam, A., Leung-Kuen Au, S., Chak-Lui Wong, C., Wei, L., Man-Fong Lee, J., He, X., Oi-Lin Ng, I. and Wong, C.-M. (2013), Histone lysine methyltransferase, suppressor of variegation 3-9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125b. Hepatology, 57: 637–647. doi: 10.1002/hep.26083
Potential conflict of interest: Nothing to report.
The study was supported by the University of Hong Kong Seed Funding Program for Basic Research (200711159020; to C.M.W.), the Research Grants Council General Research Fund (HKU 778508M; to C.M.W.), and the Research Grants Council Collaborative Research Fund (HKU 1/06C and HKU 7-CRG/09; to I.O.L.N.). I.O.L.N. is a Loke Yew Endowed Professor in Pathology.
- Issue published online: 5 FEB 2013
- Article first published online: 6 DEC 2012
- Accepted manuscript online: 18 SEP 2012 06:12AM EST
- Manuscript Accepted: 6 SEP 2012
- Manuscript Received: 8 MAY 2012
Hepatocellular carcinoma (HCC) is a major liver malignancy. We previously demonstrated that deregulation of epigenetic regulators is a common event in human HCC. Suppressor of variegation 3-9 homolog 1 (SUV39H1), the prototype of histone methyltransferase, is the major enzyme responsible for histone H3 lysine 9 trimethylation, which, essentially, is involved in heterochromatin formation, chromosome segregation, and mitotic progression. However, the implication of SUV39H1 in hepatocarcinogenesis remains elusive. In this study, we found that SUV39H1 was frequently up-regulated in human HCCs and was significantly associated with increased Ki67 expression (P < 0.001) and the presence of venous invasion (P = 0.017). To investigate the role of SUV39H1 in HCC development, both gain- and loss-of-function models were established. SUV39H1 overexpression remarkably enhanced HCC cell clonogenicity, whereas knockdown of SUV39H1 substantially suppressed HCC cell proliferation and induced cell senescence. In addition, ectopic expression of SUV39H1 increased the migratory ability of HCC cells, whereas a reduced migration rate was observed in SUV39H1 knockdown cells. The significance of SUV39H1 in HCC was further demonstrated in a nude mice model; SUV39H1 knockdown drastically inhibited in vivo tumorigenicity and abolished pulmonary metastasis of HCC cells. We also identified microRNA-125b (miR-125b) as a post-transcriptional regulator of SUV39H1. Ectopic expression of miR-125b inhibited SUV39H1 3'-untranslated-region–coupled luciferase activity and suppressed endogenous SUV39H1 expression at both messenger RNA and protein levels. We have previously reported frequent down-regulation of miR-125b in HCC. Interestingly, miR-125b level was found to be inversely correlated with SUV39H1 expression (P = 0.001) in clinical specimens. Our observations suggested that miR-125b down-regulation may account for the aberrant SUV39H1 level in HCC. Conclusion: Our study demonstrated that SUV39H1 up-regulation contributed to HCC development and metastasis. The tumor-suppressive miR-125b served as a negative regulator of SUV39H1. (HEPATOLOGY 2013)