SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells.

Yang Cui,Andrew T M Vaughan,Chen Hou,Wenyan Sun,Jing Wu,Jian Jian Li,Shiyong Li,Lili Qin,Xuan Qu,Jiankang Liu,Xianglin Shi

doi:10.1371/journal.pone.0129834

Yang Cui, Andrew T M Vaughan + Show 9 more

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https://doi.org/10.1371/journal.pone.0129834

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Abstract

SIRT3 is a key NAD+-dependent protein deacetylase in the mitochondria of mammalian cells, functioning to prevent cell aging and transformation via regulation of mitochondrial metabolic homeostasis. However, SIRT3 is also found to express in some human tumors; its role in these SIRT3-expressing tumor cells needs to be elucidated. This study demonstrated that the expression of SIRT3 was elevated in a group of gastric cancer cells compared to normal gastric epithelial cells. Although SIRT3 expression levels were increased in the gastric tumor tissues compared to the adjacent non-tumor tissues, SIRT3 positive cancer cells were more frequently detected in the intestinal type gastric cancers than the diffuse type gastric cancers, indicating that SIRT3 is linked with subtypes of gastric cancer. Overexpression of SIRT3 promoted cell proliferation and enhanced ATP generation, glucose uptake, glycogen formation, MnSOD activity and lactate production, which were inhibited by SIRT3 knockdown, indicating that SIRT3 plays a role in reprogramming the bioenergetics in gastric tumor cells. Further analysis revealed that SIRT3 interacted with and deacetylated the lactate dehydrogenase A (LDHA), a key protein in regulating anaerobic glycolysis, enhancing LDHA activity. In consistence, a cluster of glycolysis-associated genes was upregulated in the SIRT3-overexpressing gastric tumor cells. Thus, in addition to the well-documented SIRT3-mediated mitochondrial homeostasis in normal cells, SIRT3 may enhance glycolysis and cell proliferation in SIRT3-expressing cancer cells.

Highlights

Sirtuins, a family of NAD+-dependent histone deacetylases (HDACs) in mammalian cells, are implicated in a wide range of physical processes including cell survival, apoptosis, metabolism, stress responses, aging and longevity [1,2]
We found that SIRT3 protein levels were elevated in all 4 gastric cancer cell lines compared to the immortalized gastric epithelial GES-1 cells (AGS, 1.9-fold; SGC-7901, 1.5-fold; MGC-803, 2.0-fold; and HGC-27, 1.8-fold compared to GES-1 cells) (Fig 1A)
SIRT3 expression in intestinal type of tumor tissues (15 cases; 93.3% strong positive and 6.6% weak positive) was significantly higher than that in diffuse type of tumor tissues (14 cases; 14.3% strong positive, 78.6% weak positive and 7.1% negative) (Fig 1C and 1E, S1B Fig). These results suggest that SIRT3 expression is increased in some tumors compared with related normal tissues and SIRT3 expression may be vary in individual tumors, which need to be further investigated

Summary

Introduction

A family of NAD+-dependent histone deacetylases (HDACs) in mammalian cells, are implicated in a wide range of physical processes including cell survival, apoptosis, metabolism, stress responses, aging and longevity [1,2]. Among seven sirtuin members (SIRT1–7), SIRT3 is the best characterized mitochondrial sirtuin, functioning to regulate mitochondrial proteins

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