1. Academic Validation
  2. OGDH mediates the inhibition of SIRT5 on cell proliferation and migration of gastric cancer

OGDH mediates the inhibition of SIRT5 on cell proliferation and migration of gastric cancer

  • Exp Cell Res. 2019 Sep 15;382(2):111483. doi: 10.1016/j.yexcr.2019.06.028.
Xin Lu 1 Pengfei Yang 1 Xinrui Zhao 1 Mingzu Jiang 2 Sijun Hu 2 Yanan Ouyang 1 Li Zeng 1 Jing Wu 3
Affiliations

Affiliations

  • 1 Biomedical-information Engineering Laboratory of State Ministry of Education, Shaanxi Key Laboratory of Biomedical Engineering, School of Life and Science Technology, Xi'an Jiaotong University, 28 Xian Ning Western Road, Xi'an, Shaanxi, 710049, China.
  • 2 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
  • 3 Biomedical-information Engineering Laboratory of State Ministry of Education, Shaanxi Key Laboratory of Biomedical Engineering, School of Life and Science Technology, Xi'an Jiaotong University, 28 Xian Ning Western Road, Xi'an, Shaanxi, 710049, China. Electronic address: jing_wu@mail.xjtu.edu.cn.
Abstract

SIRT5 has a wide range of functions in different cellular processes such as glycolysis, TCA cycle and antioxidant defense, which mediates lysine desuccinylation, deglutarylation and demalonylation. Recent evidences have implicated that SIRT5 is a potential suppressor of gastric Cancer (GC). However, the underlying mechanism of SIRT5 in gastric Cancer is still unclear. Here, we show that SIRT5 expression is significantly decreased in human GC tissues. Functional analysis demonstrates that SIRT5 inhibits cell growth in vitro and in vivo, arrests the cell cycle in G1/S transition, and suppresses migration and invasion of GC cells via regulating epithelial-to-mesenchymal transition. Mechanistically, we demonstrate that there is the direct interaction between SIRT5 and 2-oxoglutarate dehydrogenase (OGDH), and desuccinylation of OGDH by SIRT5 inhibits the activity of OGDH complex. Further studies of the relationship between SIRT5 and OGDH show OGDH inhibition by succinyl phosphonate (SP) or siRNA suppresses the increase in cell growth and migration induced by SIRT5 deletion. Moreover, SIRT5 decreases mitochondrial membrane potential (ΔΨm), ATP products and increases the ROS levels and NADP/NADPH ratio in GC cells through the inhibition of OGDH complex activity. Therefore, SIRT5 suppresses GC cell growth and migration through desuccinylating OGDH and inhibiting OGDH complex activity to disturb mitochondrial functions and redox status.

Keywords

2-Oxoglutarate dehydrogenase; Desuccinylation; Gastric cancer; Mitochondrial function; Redox status; SIRT5.

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