title: SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein-Dependent Apoptotic Pathway.
abstract: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).
  
  
  
  The expression of SIRT6 in 60 paired paraffin-embedded HCC tissues and adjacent nontumoral liver tissues was examined by immunohistochemistry. The expression of SIRT6 in 101 paired frozen HCC tissues and adjacent nontumoral liver tissues was analyzed by Western blotting analysis and qPCR. The biologic consequences of overexpression and knockdown of SIRT6 in HCC cell lines were studied in vitro and in vivo
  
  
  
  SIRT6 expression was frequently upregulated in clinical HCC samples, and its expression was highly associated with tumor grade (P = 0.02), tumor size (P = 0.02), vascular invasion (P = 0.004), and shorter survival (P = 0.024). Depletion of SIRT6 from multiple liver cancer cell lines inhibited their growth and induced apoptosis in vitro At the molecular level, we observed that the activation of the BCL2-associated X protein (Bax) signaling pathway, a major pathway that determines cancer cell apoptosis, is regulated by SIRT6 via its deacetylase activity. SIRT6 was recruited to the promoter of Bax, where it deacetylated histone 3 lysine 9 and suppressed its promoter activity. Binding of transcription factors (p53 and E2F-1) to Bax promoter was also generally increased in SIRT6-depleted cells. In mouse xenografts, SIRT6 suppression inhibited tumor growth and induced apoptosis. Finally, there is a negative correlation between SIRT6 and Bax mRNA expressions in human HCC samples.
  
  
  
  SIRT6 is an important protumorigenic factor in liver carcinogenesis. Thus, the therapeutic targeting of SIRT6 may offer options for HCC treatment. Clin Cancer Res; 22(13); 3372-82. ©2016 AACR.
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China.
authors: Long-Kuan
authors: LK
authors: Ran
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Yong
authors: Y
authors: Chen
authors: Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China.
authors: Zhen-Zhen
authors: ZZ
authors: Zhang
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Na-Na
authors: NN
authors: Tao
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Ji-Hua
authors: JH
authors: Ren
authors: Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China.
authors: Li
authors: L
authors: Zhou
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Hua
authors: H
authors: Tang
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Xiang
authors: X
authors: Chen
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Ke
authors: K
authors: Chen
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors: Wan-Yu
authors: WY
authors: Li
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China. yixin_xinyuan@163.com ahuang1964@163.com.
authors: Ai-Long
authors: AL
authors: Huang
authors: Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. yixin_xinyuan@163.com ahuang1964@163.com.
authors: Juan
authors: J
authors: Chen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000502:physiology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D037761:Sirtuins / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D006657:Histones; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D004317:Doxorubicin; C516592:SIRT6 protein, human; D037761:Sirtuins