Abstract
BackgroundGlutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; however, its role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is largely unknown. We aimed to assess the role of GSTZ1 in HCC and to reveal the underlying mechanisms, which may contribute to finding a potential therapeutic strategy against HCC.MethodsWe first analyzed GSTZ1 expression levels in paired human HCC and adjacent normal tissue specimens and the prognostic effect of GSTZ1 on HCC patients. Thereafter, we evaluated the role of GSTZ1 in aerobic glycolysis in HCC cells on the basis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Furthermore, we assessed the effect of GSTZ1 on HCC proliferation, glutathione (GSH) concentration, levels of reactive oxygen species (ROS), and nuclear factor erythroid 2-related factor 2 (NRF2) signaling via gain- and loss- of GSTZ1 function in vitro. Moreover, we investigated the effect of GSTZ1 on diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) induced hepatocarcinogenesis in a mouse model of HCC.ResultsGSTZ1 was downregulated in HCC, thus indicating a poor prognosis. GSTZ1 deficiency significantly promoted hepatoma cell proliferation and aerobic glycolysis in HCC cells. Moreover, loss of GSTZ1 function depleted GSH, increased ROS levels, and enhanced lipid peroxidation, thus activating the NRF2-mediated antioxidant pathway. Furthermore, Gstz1 knockout in mice promoted DEN/CCl4-induced hepatocarcinogenesis via activation of the NRF2 signaling pathway. Furthermore, the antioxidant agent N-acetylcysteine and NRF2 inhibitor brusatol effectively suppressed the growth of Gstz1-knockout HepG2 cells and HCC progression in Gstz1−/− mice.ConclusionsGSTZ1 serves as a tumor suppressor in HCC. GSH depletion caused by GSTZ1 deficiency elevates oxidative stress, thus constitutively activating the NRF2 antioxidant response pathway and accelerating HCC progression. Targeting the NRF2 signaling pathway may be a promising therapeutic approach for this subset of HCC.
Highlights
Glutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism
We evaluated the role of GSTZ1 in aerobic glycolysis in hepatocellular carcinoma (HCC) cells on the basis of the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) and assessed its effect on HCC proliferation, GSH concentration, reactive oxygen species (ROS) levels, and nuclear factor erythroid 2-related factor 2 (NRF2) signaling via gain and loss of GSTZ1 function in vitro
GSTZ1 downregulation in HCC predicts a poor patient prognosis To evaluate intratumor GSTZ1 deregulation, we compared its expression between tumor tissue and tumoradjacent normal tissue samples with mRNA-Seq data from The Cancer Genome Atlas (TCGA) database using Firebrowse (Fig. 1b)
Summary
Glutathione S-transferase zeta 1 (GSTZ1) is the penultimate enzyme in phenylalanine/tyrosine catabolism. GSTZ1 is dysregulated in cancers; its role in tumorigenesis and progression of hepatocellular carcinoma (HCC) is largely unknown. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide [1]. Similar to all malignant tumors, HCC is a multistep and multi-factorial disease. The Warburg effect, the first reported metabolic change in tumors, has provided novel insights into tumorigenesis, and metabolic reprogramming has been considered a new hallmark of cancer [2]. Hundreds of consistently deregulated metabolic genes have been identified in HCC in patients [3]. Restoration of these altered metabolic pathways may provide novel insights into cancer therapeutic approaches [4]
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