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

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.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

Lu X,Yang P,Zhao X,Jiang M,Hu S,Ouyang Y,Zeng L,Wu J

doi

10.1016/j.yexcr.2019.06.028

subject

Has Abstract

pub_date

2019-09-15 00:00:00

pages

111483

issue

2

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(19)30324-6

journal_volume

382

pub_type

杂志文章

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