SIRT2 Promotes The Migration And Invasion Of Gastric Cancer By Increasing PEPCK1-related Metabolism

BackgroundMetastasis is the most important feature of gastric cancer（GC）and the most widely recognized reason for GC-related deaths.Unfortunately,the underlying mechanism behind this metastasis remains unknown.Mounting evidence suggests the dynamic regulatory role of sirtuin2（SIRT2）,a histone deacetylase（HDAC）,in cell migration and invasion.The relationship between the expression of SIRT2 and the malignant phenotypes of gastric cancer remains uncertain,and the underlying molecular mechanisms need to be further explored.The present study aims to evaluate the biological function of SIRT2 in GC and identify the target of SIRT2 as well as evaluate its therapeutic efficacy.MethodsWe investigated the SIRT2 levels in GC tissues and adjacent normal tissues as well as their relationship with prognosis.CCK8,colony-formation and transwell assays were performed to evaluate the proliferation and metastasis in GC cell lines that SIRT2was overexpressed,knockdown,and inhibited by SirReal2,respectively.The underlying molecular mechanisms were determined by western bolt analysis.Metabolism mitochondrial oxidative phosphorylation analysis,membrane potential assay and ¹³C metabolite labeling analysis were used to explore cell metabolism.We further investigated the roles of SIRT2 expression for malignant phenotype of gastric cancer through xenograft models.ResultsWe found that SIRT2 was upregulated in GC tissues compared to adjacent normal tissues,and this was correlated with reduced patient survival.Although CCK8 and colony-formation assays showed that SIRT2 overexpression,knockdown and inhibition by SirReal2 marginally promoted proliferation in GC cell lines,Transwell assays suggested that the migration and invasion abilities of gastric cancer cells were positively correlated with the expression levels of SIRT2.We demonstrated both in vitro and in vivo that SirReal2 could inhibit the deacetylation activity of SIRT2 and its downstream target PEPCK1,which is related to mitochondrial metabolism and RAS/ERK/JNK/MMP-9 pathway.ConclusionSIRT2 increased PEPCK1 protein levels and mitochondrial activity,as well as induced cell migration and invasion by activating the RAS/ERK/JNK/MMP-9 pathway.SIRT2 is expected to be a new research target in further study of the internal mechanisms of gastric cancer metabolism and metastasis.