Article first published online: 26 APR 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 57, Issue 6, pages 2287–2298, June 2013
How to Cite
Chen, J., Chan, A. W.H., To, K.-F., Chen, W., Zhang, Z., Ren, J., Song, C., Cheung, Y.-S., Lai, P. B.S., Cheng, S.-H., Ng, M. H.L., Huang, A. and Ko, B. C.B. (2013), SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling. Hepatology, 57: 2287–2298. doi: 10.1002/hep.26278
Potential conflict of interest: Nothing to report.
This work is supported by the Research Grant Council (grant nos.: CUHK 466109 and 467210) and the National Natural Science Foundation of China (grant no.; 81272764) to B.C.B.K; and National Science and Technology Major Project of China (grant no.:2013ZX10002002, 2012ZX10002005) to A.H.
- Issue published online: 12 JUN 2013
- Article first published online: 26 APR 2013
- Accepted manuscript online: 24 JAN 2013 12:31PM EST
- Manuscript Accepted: 9 DEC 2012
- Manuscript Received: 21 AUG 2012
Sirtuin 1 (SIRT1) has been implicated in telomere maintenance and the growth of hepatocellular carcinoma (HCC). Nevertheless, the role of other sirtuins in the pathogenesis of HCC remains elusive. We found that sirtuin 2 (SIRT2), another member of the sirtuin family, also contributes to cell motility and invasiveness of HCC. SIRT2 is up-regulated in HCC cell lines and in a subset of human HCC tissues (23/45). Up-regulations of SIRT2 in primary HCC tumors were significantly correlated with the presence of microscopic vascular invasion (P = 0.001), a more advanced tumor stage (P = 0.004), and shorter overall survival (P = 0.0499). Functional studies by short hairpin RNA–mediated suppression of SIRT2 expression in HCC cell lines revealed significant inhibition of motility and invasiveness. Depletion of SIRT2 also led to the regression of epithelial-mesenchymal transition (EMT) phenotypes, whereas the ectopic expression of SIRT2 in the immortalized hepatocyte cell line L02 promoted cell motility and invasiveness. Mechanistic studies revealed that SIRT2 regulates the deacetylation and activation of protein kinase B, which subsequently impinges on the glycogen synthase kinase-3β/β-catenin signaling pathway to regulate EMT. Conclusions: Our findings have uncovered a novel role for SIRT2 in HCC metastasis, and provide a rationale to explore the use of sirtuin inhibitors in HCC therapy. (HEPATOLOGY 2013;)