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

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.

SIRT3是哺乳动物细胞线粒体中关键的烟酰胺腺嘌呤二核苷酸（NAD+）依赖性蛋白质去乙酰化酶，通过调控线粒体代谢稳态发挥抑制细胞衰老与恶性转化的功能。然而，研究发现SIRT3在部分人类肿瘤中亦有表达，其在这些表达SIRT3的肿瘤细胞中的功能尚待阐明。本研究证实，相较于正常胃上皮细胞，一组胃癌细胞中的SIRT3表达水平显著升高。尽管相较于癌旁非肿瘤组织，胃肿瘤组织中的SIRT3表达水平有所上调，但肠型胃癌中SIRT3阳性癌细胞的检出率显著高于弥漫型胃癌，这表明SIRT3与胃癌亚型存在关联。过表达SIRT3可促进细胞增殖，并增强ATP生成、葡萄糖摄取、糖原合成、锰超氧化物歧化酶（MnSOD）活性及乳酸产生；上述效应可被SIRT3敲低所抑制，提示SIRT3参与重编程胃癌细胞的生物能学过程。进一步分析显示，SIRT3可与乳酸脱氢酶A（LDHA）结合并使其去乙酰化，而LDHA是调控无氧糖酵解的关键蛋白，可增强LDHA的活性。与此一致的是，在过表达SIRT3的胃癌细胞中，一组糖酵解相关基因的表达显著上调。综上，除了在正常细胞中已被广泛证实的、由SIRT3介导的线粒体稳态调控之外，SIRT3或可在表达SIRT3的癌细胞中增强糖酵解与细胞增殖。