SIRT6 Overexpression Potentiates Apoptosis Evasion in Hepatocellular Carcinoma via BCL2-Associated X Protein–Dependent Apoptotic Pathway
Long-Kuan Ran1,2, Yong Chen3, Zhen-Zhen Zhang4, Na-Na Tao1, Ji-Hua Ren1, Li Zhou5, Hua Tang1,Xiang Chen1, Ke Chen1, Wan-Yu Li1, Ai-Long Huang1,2,*, and Juan Chen1,*1 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.
2 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China.
3 Department of Hepatobiliary Surgery, First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
4 Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing, China.
5 Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China.
Juan Chen, The Second Affiliated Hospital, 1# Medical Road, Yuzhong District, Chongqing 40016, China. Phone: 86-23-68815112; Fax: 86-23-68486780; E-mail: email@example.com; or Ai-Long Huang, Phone: 86-23-68818112; Fax: 86-23-68486780; Email: firstname.lastname@example.org
L.-K. Ran, Y. Chen, and Z.-Z. Zhang contributed equally to this article.
Purpose: To characterize the functional role of SIRT6 in hepatocellular carcinoma (HCC).
Experimental Design: 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.
Results: 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.
Conclusions: 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.
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