Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer by<i>Helicobacter pylori</i>oncoprotein CagA

Abstract

Injection of the <i>Helicobacter pylori</i> cytotoxin-associated gene A (CagA) is closely associated with the development of chronic gastritis and gastric cancer. Individuals infected with <i>H. pylori</i> possessing the CagA protein produce more reactive oxygen species (ROS) and show an increased risk of developing gastric cancer. Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases and mitochondrial SIRT3 is known to be a tumor suppressor via its ability to suppress ROS and hypoxia inducible factor 1α (HIF-1α). However, it is unclear whether increased ROS production by <i>H. pylori</i> is regulated by SIRT3 followed by HIF-1α regulation and whether intracellular CagA acts as a regulator thereof. In this study, we investigated correlations among SIRT3, ROS, and HIF-1α in <i>H. pylori</i>-infected gastric epithelial cells. We observed that SIRT3-deficient AGS cells induce HIF-1α protein stabilization and augmented transcriptional activity under hypoxic conditions. In CagA ^<i>+</i><i>H. pylori</i> infected cells, CagA protein localized to mitochondria where it subsequently suppressed SIRT3 proteins. CagA ^<i>+</i><i>H. pylori</i> infection also increased HIF-1α activity through the ROS production induced by the downregulated SIRT3 activity, which is similar to the hypoxic condition in gastric epithelial cells. In contrast, overexpression of SIRT3 inhibited the HIF-1α protein stabilization and attenuated the increase in HIF-1α transcriptional activity under hypoxic conditions. Moreover, CagA ^<i>+</i><i>H. pylori</i> attenuated HIF-1α stability and decreased transcriptional activity in SIRT3-overexpressing gastric epithelial cells. Taken together, these findings provide valuable insights into the potential role of SIRT3 in CagA ^<i>+</i><i>H. pylori</i>-mediated gastric carcinogenesis and a possible target for cancer prevention via inhibition of HIF-1α.