SIRT2 Overexpression in Hepatocellular Carcinoma Mediates Epithelial to Mesenchymal Transition via Akt/GSK‐3β/β‐catenin Signaling.

Abstract

The yeast silent information regulator 2 (SIR2) is a histone deacetylase that utilizes NAD+ as a cofactor for its functions. In mammals, SIR2 is represented by seven homologues (SIRT1–7). We found that Sirtuin 2 (SIRT2) contributes to cell motility and invasiveness of HCC. SIRT2 is upregulated 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), more advanced tumor stage (p=0.004) and shorter overall survival (p=0.0499). Functional studies by shRNA‐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 enhanced the expression of EMT markers, and promoted cell motility and invasiveness. Mechanistic studies revealed that SIRT2 regulates the deacetylation and activation of Akt, which subsequently impinges on GSK‐3β/β‐catenin signaling pathway to regulate EMT. Concordantly, we showed that there is a positive correlation between the level of SIRT2 and β‐catenin in human HCC. Our findings uncover a novel role of SIRT2 in HCC metastasis, and provide a rationale to explore the use of sirtuin inhibitors in HCC therapy.