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SIRT5 Promotes Hepatocellular Carcinoma Progression by Regulating Mitochondrial Apoptosis

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SIRT5 Promotes Hepatocellular Carcinoma Progression by Regulating Mitochondrial Apoptosis 1 SIRT5 Promotes Hepatocellular Carcinoma 2 Progression by Regulating Mitochondrial Apoptosis 3 Rixin Zhang1*, Chengye Wang1*, Yu Tian1,2, Yifan Yao1, Jiakai Mao1, Haibo Wang1, 4 Zhenghan Li1, Yakun Xu1, Mingliang Ye3, Liming Wang1 5 6 1. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Second Hospital of 7 Dalian Medical University, NO.467, Zhongshan Road, Dalian, Liaoning 116023, China. 8 2. Department of Vascular Surgery, The Second Hospital of Dalian Medical University, NO.467, 9 Zhongshan Road, Dalian, Liaoning 116023, China. 10 3. CAS Key Lab of Separation Sciences for Analytical Chemistry, National Chromatographic Research 11 and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, NO.457, 12 Zhongshan Road, Dalian, Liaoning 116023, China. 13 *These authors have contributed equally to this work. 14 Corresponding author: Liming Wang, email: [email protected],Tel # +86-17709870007 15 16 Abstract 17 SIRT5 belongs to a family of NAD+-dependent lysine deacetylases called sirtuins. 18 Although accumulating evidence indicates SIRT5 upregulation in cancers, including 19 liver cancer, the detailed roles and mechanisms remain to be revealed. Hepatocellular 20 carcinoma (HCC) is the second leading cause of cancer-related deaths among men 21 worldwide, and finding effective targets for HCC treatment and prevention is urgently 22 needed. In the present study, we confirmed that mitochondrial sirtuins, particularly 23 SIRT5, are more highly expressed in HCC cell lines than in normal liver cell lines. 24 Moreover, SIRT5 knockdown suppresses HCC cell proliferation and SIRT5 25 overexpression promotes HCC cell proliferation. Furthermore, we verified that SIRT5 26 knockdown increases HCC cell apoptosis via the mitochondrial pathway. By co-IP and 27 western blotting, we illustrated that SIRT5 deacetylates cytochrome c thus regulating 28 HCC cell apoptosis. Taken together, our findings suggest that SIRT5 may function as a 29 prognostic factor and drug target for HCC treatment. 30 31 Key words: SIRT5, HCC, Cytochrome c, Acetylation 32 Introduction 33 Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent 34 lysine deacetylases. SIRTs are characterized by a highly conserved SIRT catalytic core 35 domain [1]. SITRs are mammalian orthologues of the silent information regulator (SIR) 36 2 protein which was the first reported sirtuin gene from Saccharomyces cerevisiae [2, 37 3]. Seven SIRTs (SIRT1-7) exist in humans, and these SIRTs have different locations. 38 SIRT1, SIRT6 and SIRT7 are present primarily in the nucleus. SIRT2 exists in the 39 cytoplasm, while SIRT3, SIRT4 and SIRT5 are localized in mitochondria [4]. SIRTs 40 participate in diverse cellular processes, such as cell fate, DNA stress repair, ageing and 41 metabolism [5, 6] and play important roles in various diseases, such as 42 neurodegenerative diseases [7, 8], cardiovascular diseases [9] and type Ⅱ diabetes [10]. 43 SIRT5, a member of the SIRT family, is localized mainly in the mitochondria. SIRT5 44 has diverse catalytic activities of desuccinylation, deglutarylation and demalonylation, 45 as well as roles in mitochondrial metabolism [11]. Currently, the most important roles 46 of SIRT5 has been reported in the urea cycle in mitochondria. SIRT5 can deacetylate 47 and stimulate carbamoyl phosphate synthetase (CPS1), leading to ammonia 48 detoxification [12]. SIRT5 could regulate fatty acid metabolism through desuccinylase 49 hydroxyl-coenzyme A dehydrogenase (HADH) which is an essential enzyme in fatty 50 acid metabolism [13]. In mitochondrial oxidative phosphorylation, SIRT5 suppresses 51 the biochemical activity of the important TCA cycle enzyme succinate dehydrogenase 52 (SDH) and reduces the mitochondrial respiration driven by SDH [13]. Hala et al. 53 reported that SIRT5 deletion enhanced mitochondrial DRP1 accumulation, leading to 54 mitochondrial fragmentation and degradation during autophagy[14]. Excess 55 mitochondrial reactive oxygen species (ROS) increase cellular oxidative stress, and 56 SIRT5 could enhance cellular antioxidant defense by deglutarylating glucose-6- 57 phosphate dehydrogenase (G6PD) and desuccinylating isocitrate dehydrogenase 2 58 (IDH2) [15]. SIRT5 could also eliminate ROS through desuccinylating and activating 59 Cu/Zn superoxide dismutase 1 (SOD1) [16]. Furthermore, SIRT5 was also reported to 60 be a regulator of mitochondrial energy metabolism, and SIRT5 overexpression 61 increased ATP synthesis and oxygen consumption in HCC cell line HepG2 [17]. 62 Researches on the relation between SIRT and cancers has been continuous since SIRTs 63 were identified [18, 19]. However, correlations between SIRT5 and cancers have rarely 64 been reported. The roles of SIRT5 in cancers were studied and revealed only recently. 65 Existing evidence suggests that SIRT5 functions as an oncogene. In non-small cell lung 66 cancer (NSCLC) SIRT5 could promote cell growth and enhance drug resistance [20]. 67 Based on TCGA data, Gong et al revealed that SIRT5 was highly expressed in 68 squamous cell carcinoma and that high SIRT5 expression was associated with poor 69 overall survival in NSCLC patients [21]. In colorectal cancer (CRC), SIRT5 also 70 promotes colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation- 71 dependent manner [22]. Moreover, SIRT5 could promote CRC cell respiration, 72 proliferation and tumour growth by deacetylating lactate dehydrogenase B (LDHB), a 73 glycolytic enzyme that catalyses the conversion of lactate and NAD+ to pyruvate [23]. 74 In triple-negative breast cancer (TNBC), SIRT5 is upregulated markedly and high 75 SIRT5 expression has been associated with poor clinical prognosis [24]. SIRT5 could 76 also control ammonia production by regulating glutaminase and glutamine metabolism, 77 resulting in ammonia-induced autophagy and mitophagy in breast carcinoma and 78 mouse myoblastoma cells [25]. SIRT5 has been reported to increase SHMT2 activity 79 and enhance serine catabolism, leading to tumor cell proliferation [26]. In HEK293T 80 cells, SIRT5 could bind to and desuccinylate pyruvate kinase M2 (PKM2), thus 81 stimulating in cell proliferation and tumor growth [27]. On the other hand, SIRT5 has 82 also reported to suppress the tumor progression. In gastric cancer, SIRT5 inhibites 83 gastric cancer cell proliferation by suppressing aerobic glycolysis [28]. Furthermore, 84 SIRT5 could facilitate S100A10 degradation, thus inhibiting the role of S100A10 in 85 promoting gastric cancer invasion and migration [29]. Consequently, additional studies 86 should be peformed to explore the positive or negative roles of SIRT5 in more cancers. 87 Primary liver cancer is the fifth most prevalent malignant tumor and the second leading 88 cause of cancer-related deaths among men worldwide, particularly in less developing 89 countries, primary liver cancer accounts for approximately 50% of the total number of 90 cases and deaths occurring in China alone [30]. According to Chinese statistical data, 91 liver cancer was estimated as the first killer and most common cancer of men younger 92 than 60 years old in 2015 [31]. Although the incidence of liver cancer has decreased 93 gradually, the estimated deaths from liver cancer still ranked fifth among all cancers in 94 males in the United States [32]. Hepatocellular carcinoma (HCC) is the most common 95 and accounts for 85-90% of total primary liver cancer cases [33]. Surgical resection 96 remains the most common therapeutic strategy for resectable HCC patients; however, 97 many advanced HCC patients are not suitable for surgery [34] and the recurrence rate 98 after surgical resection for HCC remains approximately 50-70% [35]. Liver 99 transplantation, embolization, ablation, radiation therapy and chemotherapy have 100 provieded partial curative interventions. However, only approximately 30% of HCC 101 patients meet the criteria for all the above therapies [36]; furthermore, despite so many 102 therapies, the HCC five-year survival rate is as low as 17% [37]. Therefore, identifying 103 new treatment targets or developing novel strategies for HCC management is urgently 104 needed. 105 The role of SIRT5 in cancers has not been identified completely. Before 2013, few 106 studies reported the effects of SIRT5 in HCC. Recently, an increasing number of studies 107 have gradually revealed the role of SIRT5 in HCC. In fact, high-levels of gene 108 amplification and expression have been reported for SIRT5 in liver cancer [38]. SIRT5 109 expression is upregulated in HCC tissues and cell lines, and its overexpression is 110 positively correlated with tumor size, lymph node metastasis and TNM stage. SIRT5 111 upregulation also indicates poor clinical prognosis in HCC patients. SIRT5 directly 112 targets and activates E2F transcription factor 1 (E2F1) thus promoting HCC cell 113 proliferation and invasion [39]. However, the mechanisms of SIRT5 regulation in HCC 114 need to be studied further to achieve complete understanding. 115 In the present study, we selected two HCC cell lines (Bel-7402, Huh7) to confirm the 116 effects of SIRT5 in HCC. We found that SIRT5 could facilitate HCC progression by 117 inhibiting HCC cell apoptosis. Furthermore, we revealed that SIRT5 could deacetylate 118 cytochrome c (cyt c) and regulate cyt c distribution in the cytoplasm and mitochondria 119 to suppress mitochondrial apoptosis. Our results suggest that SIRT5 is a potential 120 marker and drug target for HCC diagnosis and treatment.
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