Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer by Helicobacter pylori oncoprotein CagA

Do Yeon Lee, Dawoon E. Jung, Sung Sook Yu, Yeo Song Lee, Beom Ku Choi, Yongchan Lee

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Injection of the Helicobacter pylori cytotoxin-associated gene A (CagA) is closely associated with the development of chronic gastritis and gastric cancer. Individuals infected with H. pylori 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 H. pylori 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 H. pylori-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+ H. pylori infected cells, CagA protein localized to mitochondria where it subsequently suppressed SIRT3 proteins. CagA+ H. pylori 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+ H. pylori 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+ H. pylori-mediated gastric carcinogenesis and a possible target for cancer prevention via inhibition of HIF-1α.

Original languageEnglish
Pages (from-to)78365-78378
Number of pages14
JournalOncotarget
Volume8
Issue number45
DOIs
Publication statusPublished - 2017 Jan 1

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Hypoxia-Inducible Factor 1
Oncogene Proteins
Cytotoxins
Helicobacter pylori
Stomach Neoplasms
Reactive Oxygen Species
Genes
Stomach
Epithelial Cells
Proteins
NAD
Sirtuins
Cell Hypoxia
Helicobacter Infections
Gastritis
Neoplasms
Mitochondria
Carcinogenesis
Down-Regulation
Injections

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Lee, Do Yeon ; Jung, Dawoon E. ; Yu, Sung Sook ; Lee, Yeo Song ; Choi, Beom Ku ; Lee, Yongchan. / Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer by Helicobacter pylori oncoprotein CagA. In: Oncotarget. 2017 ; Vol. 8, No. 45. pp. 78365-78378.
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abstract = "Injection of the Helicobacter pylori cytotoxin-associated gene A (CagA) is closely associated with the development of chronic gastritis and gastric cancer. Individuals infected with H. pylori 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 H. pylori 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 H. pylori-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+ H. pylori infected cells, CagA protein localized to mitochondria where it subsequently suppressed SIRT3 proteins. CagA+ H. pylori 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+ H. pylori 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+ H. pylori-mediated gastric carcinogenesis and a possible target for cancer prevention via inhibition of HIF-1α.",
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Regulation of SIRT3 signal related metabolic reprogramming in gastric cancer by Helicobacter pylori oncoprotein CagA. / Lee, Do Yeon; Jung, Dawoon E.; Yu, Sung Sook; Lee, Yeo Song; Choi, Beom Ku; Lee, Yongchan.

In: Oncotarget, Vol. 8, No. 45, 01.01.2017, p. 78365-78378.

Research output: Contribution to journalArticle

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