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SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase‐3β/β‐catenin signaling
Author(s) -
Chen Juan,
Chan Anthony W.H.,
To KaFai,
Chen Weixian,
Zhang Zhenzhen,
Ren Jihua,
Song Chunli,
Cheung YueSun,
Lai Paul B.S.,
Cheng SukHang,
Ng Margaret H.L.,
Huang Ailong,
Ko Ben C.B.
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26278
Subject(s) - sirt2 , sirtuin , cancer research , biology , gsk 3 , epithelial–mesenchymal transition , small hairpin rna , kinase , microbiology and biotechnology , cancer , cell culture , metastasis , acetylation , gene knockdown , biochemistry , gene , genetics
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. (H EPATOLOGY 2013;)