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

Ji Hyun Seo; Somi Ryu; So Young Cheon; Seong-Jun Lee; Seong-Jun Won; Chae Dong Yim; Hyun-Jin Lee; Young-Sool Hah; Jung Je Park

doi:10.3390/cancers16020387

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

Cancers (Basel). 2024 Jan 16;16(2):387. doi: 10.3390/cancers16020387.

Authors

Ji Hyun Seo^{1

2}, Somi Ryu^{2

3}, So Young Cheon⁴, Seong-Jun Lee⁵, Seong-Jun Won^{2

3}, Chae Dong Yim^{2

3}, Hyun-Jin Lee⁶, Young-Sool Hah^{2

4}, Jung Je Park^{2

3

4}

Affiliations

¹ Department of Pediatrics, Institute of Health Science, College of Medicine, Gyeongsang National University, Jinju 52725, Republic of Korea.
² Institute of Medical Science, Gyeongsang National University, Jinju 52725, Republic of Korea.
³ Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Gyeongsang National University, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea.
⁴ Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea.
⁵ Department of Convergence of Medical Sciences, Gyeongsang National University, Jinju 52725, Republic of Korea.
⁶ Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Chung-Ang University, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong 06973, Republic of Korea.

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.

Keywords: Sirtuin1; Sirtuin6; gastric cancer; sirtuins.

Grants and funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2020R1I1A3067325), the National Research Foundation of Korea (NRF-2020R1A2C1012038, NRF-2017R1A2B4010122, and NRF-2021R1F1A1056420), and the Biomedical Research Institute fund (GNUHBRIF-2018-0012) of Gyeongsang National University Hospital.