SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1α-mediated mitochondrial biogenesis
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Yuming Li1,*, Shangcheng Xu2,*, Jing Li1, Lu Zheng1, Min Feng2, Xiaoya Wang3, Keqiang Han1, Huifeng Pi2, Min Li2, Xiaobing Huang1, Nan You1, Yewang Tian1, Guohua Zuo1, Hongyan Li1, Hongzhi Zhao1, Ping Deng2, Zhengping Yu2, Zhou Zhou2, Ping Liang1
1Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China
2Department of Occupational Health, Third Military Medical University, Chongqing 400038, China
3Department of Military Nursing, School of Nursing, Third Military Medical University, Chongqing 400038, China
*These authors contributed equally to this work
Ping Liang, e-mail: [email protected]
Zhou Zhou, e-mail: [email protected]
Keywords: SIRT1, PGC-1α, mitochondrial biogenesis, metastasis, hepatocellular carcinoma
Received: November 25, 2015 Accepted: March 28, 2016 Published: April 12, 2016
SIRT1 is a multifaceted NAD+-dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a novel mechanism of SIRT1-induced hepatocellular carcinoma (HCC) metastasis. SIRT1 overexpression was frequently detected in human HCC specimens and was associated with microvascular invasion (P = 0.0039), advanced tumor node metastasis (TNM) stages (P = 0.0016), HCC recurrence (P = 0.021) and poor outcomes (P = 0.039). Lentivirus-mediated knockdown of SIRT1 in MHCC97H cells reduced invasion and metastasis in vitro and in vivo. SIRT1 depletion attenuated mitochondrial biogenesis and adenosine triphosphate (ATP) production but did not affect epithelial-mesenchymal transition. Elevated SIRT1 expression strongly correlated with the upregulation of PGC-1α in HCC specimens, and ectopic expression of SIRT1 increased PGC-1α levels. In cell assays and an orthotopic transplantation model, PGC-1α overexpression reversed the inhibitory effects of SIRT1 depletion on invasion and metastasis by enhancing mitochondrial biogenesis. These findings reveal the involvement of SIRT1 in HCC metastasis and provide a rationale for exploring therapeutic targets against the SIRT1/PGC-1α axis.
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