Hepatology
Hepatobiliary Malignancies
SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling
Chen, Juan1; Chan, Anthony W.H.2; To, Ka-Fai2,3; Chen, Weixian4; Zhang, Zhenzhen5; Ren, Jihua1; Song, Chunli1; Cheung, Yue-Sun6; Lai, Paul B.S.6; Cheng, Suk-Hang2; Ng, Margaret H.L.2; Huang, Ailong1,**,‡; Ko, Ben C.B.1,2,3,*,†
1The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
2Departments of Anatomical and Cellular Pathology
3The State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
4Department of Clinical Laboratory, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
5Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China
6Departments of Surgery, The Chinese University of Hong Kong, Hong Kong, China
*Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Room 38019, Clinical Sciences Building, The Prince of Wales Hospital, Shatin, Hong Kong, China
**The Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China
Email:[email protected][email protected]
Received 21 August 2012; Accepted 9 December 2012
View this article online atwileyonlinelibrary.com.
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.
‡Fax: (86)-02368486780
†fax: 852-2637-6274
Abstract
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.