Sirtuin 3 Inhibits Hepatocellular Carcinoma Growth Through the Glycogen Synthase Kinase-3β/BCL2-associated X Protein-dependent Apoptotic Pathway

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2015 Apr 28

PMID 25915842

Citations 34

Authors

C-L Song

H Tang

L-K Ran

B C B Ko

Z-Z Zhang

X Chen

J-H Ren

N-N Tao

W-Y Li

A-L Huang

J Chen

Affiliations

Soon will be listed here.

Abstract

SIRT3 is a class III histone deacetylase that has been implicated in a variety of cancers. The role of SIRT3 in hepatocellular carcinoma (HCC) remains elusive. In this study, we found that SIRT3 expression was frequently repressed in HCC and its downregulation was closely associated with tumor grade and size. Ectopic expression of SIRT3 inhibited cell growth and induced apoptosis in HCC cells, whereas depletion of SIRT3 in immortalized hepatocyte promoted cell growth and decreased epirubicin-induced apoptosis. Mechanistic studies revealed that SIRT3 deacetylated and activated glycogen synthase kinase-3β (GSK-3β), which subsequently induced expression and mitochondrial translocation of the pro-apoptotic protein BCL2-associated X protein (Bax) to promote apoptosis. GSK-3β inhibitor or gene silencing of BAX reversed SIRT3-induced growth inhibition and apoptosis. Furthermore, SIRT3 overexpression also suppressed tumor growth in vivo. Together, this study reveals a role of SIRT3/GSK-3β/Bax signaling pathway in the suppression of HCC growth, and also suggests that targeting this pathway may represent a potential therapeutic approach for HCC treatment.

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