Sirt6-Mediated Cell Death Associated with Sirt1 Suppression in Gastric Cancer

Abstract

Simple Summary This study highlights the potential anti-cancer effects of the sirtuin (Sirt) family in gastric cancer. Among the seven mammalian sirtuin proteins, Sirt6 and Sirt1 seem to be key factors of gastric cancer cell death. To be more specific, Sirt6 overexpression in association with Sirt1 suppression induces reactive oxygen species (ROS) and mouse double minute 2 homolog (MDM2) expression, which result in cancer cell death and a reduction in tumor volume. These findings, by supporting Sirt6- and Sirt1-mediated gastric cancer cell death via ROS regulation, suggest new potential therapeutic targets for the future treatment of gastric cancer.Abstract Background: Gastric cancer, one of the leading causes of cancer-related death, is strongly associated with H. pylori infection, although other risk factors have been identified. The sirtuin (Sirt) family is involved in the tumorigenesis of gastric cancer, and sirtuins can have pro- or anti-tumorigenic effects. Methods: After determining the overall survival rate of gastric cancer patients with or without Sirt6 expression, the effect of Sirt6 upregulation was also tested using a xenograft mouse model. The regulation of Sirt6 and Sirt1, leading to the induction of mouse double minute 2 homolog (MDM2) and reactive oxygen species (ROS), was mainly analyzed using Western blotting and immunofluorescence staining, and gastric cancer cell (SNU-638) death associated with these proteins was measured using flow cytometric analysis. Results: Sirt6 overexpression led to Sirt1 suppression in gastric cancer cells, resulting in a higher level of gastric cancer cell death in vitro and a reduced tumor volume. ROS and MDM2 expression levels were upregulated by Sirt6 overexpression and/or Sirt1 suppression according to Western blot analysis. The upregulated ROS ultimately led to gastric cancer cell death as determined via Western blot and flow cytometric analysis. Conclusion: We found that the upregulation of Sirt6 suppressed Sirt1, and Sirt6- and Sirt1-induced gastric cancer cell death was mediated by ROS production. These findings highlight the potential of Sirt6 and Sirt1 as therapeutic targets for treating gastric cancer.