SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1α-mediated mitochondrial biogenesis.

// Yuming Li 1, * , Shangcheng Xu 2, * , Jing Li 1 , Lu Zheng 1 , Min Feng 2 , Xiaoya Wang 3 , Keqiang Han 1 , Huifeng Pi 2 , Min Li 2 , Xiaobing Huang 1 , Nan You 1 , Yewang Tian 1 , Guohua Zuo 1 , Hongyan Li 1 , Hongzhi Zhao 1 , Ping Deng 2 , Zhengping Yu 2 , Zhou Zhou 2 , Ping Liang 1 1 Department of Hepatobiliary Surgery, Second Affiliated Hospital of Third Military Medical University, Chongqing 400037, China 2 Department of Occupational Health, Third Military Medical University, Chongqing 400038, China 3 Department of Military Nursing, School of Nursing, Third Military Medical University, Chongqing 400038, China * These authors contributed equally to this work Correspondence to: Ping Liang, e-mail: lpxqyy@163.com Zhou Zhou, e-mail: lunazhou00@163.com Keywords: SIRT1, PGC-1α, mitochondrial biogenesis, metastasis, hepatocellular carcinoma Received: November 25, 2015      Accepted: March 28, 2016      Published: April 12, 2016 ABSTRACT 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.