Abstract
Hepatocellular carcinoma (HCC) is developed from uncontrolled cell growth after the malignant transformation of hepatocytes. The hepatitis B virus (HBV) X protein (HBx) has shown to induce cell cycle progression and hepatocarcinogenesis. A sub-fraction of HBx is localized in the mitochondria. Sirtuin 4 (SIRT4), a mitochondrial protein, has been demonstrated to play a tumor-suppressive role in many cancers, including HCC. However, little is known about the association between mitochondrial HBx and SIRT4 during hepatocarcinogenesis. We aimed to investigate the clinical significance and functional role of SIRT4 in HBV-related HCC. SIRT4 expression was significantly lower in the HCC tissues collected from 30 patients with HBV-related HCC than in normal liver tissues from control patients (p < 0.0001). TCGA data analysis indicated that SIRT4 expression was also lower in patients with HBV infection than in those without, and SIRT4 levels were positively associated with better patient survival. Similarly, HCC cell lines had lower SIRT4 expression than normal liver cell lines (all p < 0.01). Among the HCC cell lines, those harbored HBV had a lower SIRT4 expression than those without HBV (p < 0.0001). In vitro experiments revealed that stable HBx transfection suppressed SIRT4 expression in both HepG2 and Huh7 cells (both p < 0.001). Ectopic SIRT4 overexpression alone could induce cellular senescence through arresting cell-cycle progression at G2/M, and inducing cell apoptosis in HCC cells. Mechanistically, SIRT4 upregulated cell-cycle governing genes p16 and p21 protein expression, suppressed CyclinB1/Cdc2 and Cdc25c which normally induce cell-cycle progression, and suppressed survivin to induce apoptosis. Our findings demonstrate the interaction between HBV and SIRT4 in the context of HCC. SIRT4 involves in G2/M DNA damage checkpoint control and genomic stability in hepatocarcinogenesis, which could be targeted for future anticancer strategies.
Highlights
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality owing to late symptom manifestations and limited treatment options[1]
Based on the role of mitochondrial HBV X protein (HBx) in inducing oxidative stress and the tumor-suppressive function of Sirtuin 4 (SIRT4), both of which share the same mitochondrial localization, this study aimed to investigate the functional role of SIRT4 and its interaction with HBx in the development of hepatitis B virus (HBV)-related HCC
A previous report has demonstrated that suppression of SIRT4 expression promotes mitochondrial glutamine utilization to enhance HCC cell growth and HCC tumorigenesis, and knockout of SIRT4 promotes HCC lung metastasis in mice[32]
Summary
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality owing to late symptom manifestations and limited treatment options[1]. HBV DNA can randomly integrate into the host hepatocyte genome during chronic infection[6]. S, polymerase, and X genes, among which only the X gene is well preserved in the integrated HBV DNA in the host genome of HCC patients[7]. The HBV X protein (HBx) is Official journal of the Cell Death Differentiation Association. Previous studies suggest that HBx contributes to the progression of HCC by interacting with cellular proteins and altering many signaling processes including transcription regulation, signal transduction, cell-cycle progression, cellular senescence, apoptosis, and protein degradation[8,11,12,13,14]. Owing to the fact that treatment options against HCC are limited, targeting the HBxaltered molecular networks might offer new therapeutic options for early detection and treatment of this disease
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