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.

SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

“…In this report, inhibitory roles of SIRT6 in senescence were investigated using tumorigenic cell lines in a normal condition. Though a group recently reported the inhibitory role of SIRT6 in senescence using HCC cell lines, they performed all experiments under the treatment of TGF-1β/H 2 O 2 /HOCI which could induce cellular senescence[37]. In this context, senescence was induced by activating the classical p16 and p21 pathways[37].…”

“…Though a group recently reported the inhibitory role of SIRT6 in senescence using HCC cell lines, they performed all experiments under the treatment of TGF-1β/H 2 O 2 /HOCI which could induce cellular senescence[37]. In this context, senescence was induced by activating the classical p16 and p21 pathways[37]. However, our results indicated that SIRT6 depletion without the treatment of TGF-1β/H 2 O 2 /HOCI promoted cellular senescence in the p16/Rb- and p53/p21-independent manners.…”

Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C

“…Western blot assays were performed as described previously (24). The antibodies that were used are described in the Supplementary Methods.…”

The role of SIRT6 in tumors

“…16 Zhang et al 17 demonstrated that SIRT6 overexpression in HCC suppresses tumor growth by blocking extracellular signalregulated kinases (ERK) 1/2 signaling pathway. In addition, Feng et al 18 and Ran et al 19 showed that SIRT6 plays an oncogenic role in HCC. In particular, the overexpression of SIRT6 is required for induction of transforming growth factor (TGF)-β1 and H2O2/HOCl reactive oxygen species (ROS) that mediate tumorigenesis.…”

“…TGF-β1 upregulates the SIRT6 expression inducing the activation of ERK and Smad pathways, and altering the effect of these proteins on cellular senescence. 18 Ran et al 19 demonstrated an oncogenic effect of SIRT6 via chromatin remodeling. At molecular level, SIRT6 induces deacetylation of H3K9 that blocks Bcl-2-associated X protein (Bax) transcription.…”