SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC.
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.
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
Namgyu
N
Lee
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
Hye Guk
HG
Ryu
Cbs Bioscience Inc., Daejeon, Korea.
Jung-Hee
JH
Kwon
Donnelly Centre, Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, Ontario, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Dae-Kyum
DK
Kim
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.
Sae Rom
SR
Kim
Department of Surgery, Ajou University School of Medicine, Suwon, Korea.
Hee Jung
HJ
Wang
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
Kyong-Tai
KT
Kim
Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Korea.|Division of Integrative Biosciences & Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.
Kwan Yong
KY
Choi
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D004249:DNA Damage / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D037761:Sirtuins / Q000172:deficiency / Q000502:physiology*
C516592:SIRT6 protein, human; D037761:Sirtuins