title: Sirtuin 6 promotes transforming growth factor-β1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence.
abstract: Sirtuin 6 (SIRT6) can function as a tumor suppressor by suppressing aerobic glycolysis and apoptosis resistance. However, the negative effect of SIRT6 on cellular senescence implies that it may also have the potential to promote tumor development. Here we report that the upregulation of SIRT6 expression was required for transforming growth factor (TGF)-β1 and H2O2/HOCl reactive oxygen species (ROS) to promote the tumorigenicity of hepatocellular carcinoma (HCC) cells. Transforming growth factor-β1/H2O2/HOCl could upregulate SIRT6 expression in HCC cells by inducing the sustained activation of ERK and Smad pathways. Sirtuin 6 in turn abrogated the inducing effect of TGF-β1/H2O2/HOCl on cellular senescence of HCC cells, and was required for the ERK pathway to efficiently suppress the expression of p16 and p21. Sirtuin 6 altered the effect of Smad and p38 MAPK pathways on cellular senescence, and contributed to the inhibitory effect of the ERK pathway on cellular senescence. However, SIRT6 was inefficient in antagonizing the promoting effect of TGF-β1/H2O2 HOCl on aerobic glycolysis and anoikis resistance. Intriguingly, if SIRT6 expression was inhibited, the promoting effect of TGF-β1/H2O2/HOCl on aerobic glycolysis and anoikis resistance was not sufficient to enhance the tumorigenicity of HCC cells. Suppressing the upregulation of SIRT6 enabled TGF-β1/H2O2/HOCl to induce cellular senescence, thereby abrogating the enhancement of HCC cell tumorigenicity by TGF-β1/H2O2/HOCl. These results suggest that SIRT6 is required for TGF-β1/H2O2/HOCl to enhance the tumorigenicity of HCC cells, and that targeting the ERK pathway to suppress the upregulation of SIRT6 might be a potential approach in comprehensive strategies for the therapy of HCC.
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: Xin-Xia
authors: XX
authors: Feng
authors: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Jing
authors: J
authors: Luo
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: Mei
authors: M
authors: Liu
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: Wei
authors: W
authors: Yan
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: Zhen-Zhen
authors: ZZ
authors: Zhou
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: Yu-Jia
authors: YJ
authors: Xia
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: Wei
authors: W
authors: Tu
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: Pei-Yuan
authors: PY
authors: Li
authors: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Zuo-Hua
authors: ZH
authors: Feng
authors: Department of Gastroenterology, Tongji Hospital, Wuhan, China.
authors: De-An
authors: DA
authors: Tian
mesh_terms: D000818:Animals; D023102:Anoikis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D006019:Glycolysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D006997:Hypochlorous Acid / Q000378:metabolism / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008819:Mice, Nude; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: Cellular senescence; SIRT6; TGF-β1; tumor cells; tumorigenicity