Sirt6-mediated cell death associated with Sirt1 suppression in gastric cancer

Abstract

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-tumorigenic or anti-tumorigenic effects. Methods After determining the overall survival rate of gastric cancer patients with or without Sirt6 expression was determined, the effect of Sirt6 upregulation was also tested using an in vivo xenograft mouse model. The regulation of Sirt6 and Sirt1, leading to the induction of MDM2 and reactive oxygen species (ROS), was mainly analyzed with western blot and immunofluorescence staining, and gastric cancer cell (SNU-638) death associated with these proteins were measured using flow cytometric analysis. Results Sirt6 overexpression lead to Sirt1 suppression of gastric cancer cell, resulted in a higher level of gastric cancer cell death in vitro and a reduced tumor volume in vivo. The ROS and MDM2 expression levels were upregulated by Sirt6 overexpression and/or Sirt1 suppression on western blot analysis. The upregulated ROS ultimately led to gastric cancer cell death on western blot and flow cytometric analysis. Conclusion We found that 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 in gastric cancer.