Abstract
The role of Sirtuin 6 (SIRT6) as a tumor suppressor or oncogene in liver cancer remains controversial. Thus, we identified the specific role of SIRT6 in the progression of hepatocellular carcinoma (HCC). SIRT6 expression was significantly higher in HCC cell lines and HCC tissues from 138 patients than in an immortalized hepatocyte cell line, THLE-2 and non-tumor tissues, respectively. SIRT6 knockdown by shRNA suppressed the growth of HCC cells and inhibited HCC tumor growth in vivo. In addition, SIRT6 silencing significantly prevented the growth of HCC cell lines by inducing cellular senescence in the p16/Rb- and p53/p21-pathway independent manners. Microarray analysis revealed that the expression of genes involved in nucleosome assembly was apparently altered in SIRT6-depleted Hep3B cells. SIRT6 knockdown promoted G2/M phase arrest and downregulation of genes encoding histone variants associated with nucleosome assembly, which could be attributed to DNA damage. Taken together, our findings suggest that SIRT6 acts as a tumor promoter by preventing DNA damage and cellular senescence, indicating that SIRT6 represents a potential therapeutic target for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is a major histological subtype, accounting for 85–90% of primary liver cancers[1]
In order to investigate the role of Sirtuin 6 (SIRT6) in liver cancer, the protein levels of SIRT6 were compared among an immortalized hepatocyte cell line, THLE-2, and such six HCC cell lines as Hep3B, HepG2, SNU475, SK-Hep1, SNU449 and Huh-7
Our findings demonstrate the oncogenic potential of SIRT6 in HCC and suggest SIRT6 as a potential therapeutic target for HCC
Summary
Hepatocellular carcinoma (HCC) is a major histological subtype, accounting for 85–90% of primary liver cancers[1]. Incidence rates of HCC have remained high in Eastern and SouthEastern Asia and have increased in the United States and Central Europe[2]. Oncogenic Potential of SIRT6 in HCC (PJ011216012016). The funders provided support in the form of salaries for authors [NL, KYC], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. JHK is employees of CbsBioscience, whose company provided support in the form of salary for her, but did not have any additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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