1. Academic Validation
  2. O-GlcNAcylation mediates H2O2-induced apoptosis through regulation of STAT3 and FOXO1

O-GlcNAcylation mediates H2O2-induced apoptosis through regulation of STAT3 and FOXO1

  • Acta Pharmacol Sin. 2024 Jan 8. doi: 10.1038/s41401-023-01218-z.
Chen-Chun Zhang 1 2 Yuan Li 1 2 Chang-You Jiang 1 2 Qiu-Min Le 1 2 Xing Liu 1 2 Lan Ma 1 2 Fei-Fei Wang 3 4
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai, 200032, China.
  • 2 Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai, 200032, China.
  • 3 School of Basic Medical Sciences, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Neurology, Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai, 200032, China. ffwang@fudan.edu.cn.
  • 4 Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai, 200032, China. ffwang@fudan.edu.cn.
Abstract

The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced Apoptosis remain to be elucidated. Here, we show that treatment with H2O2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved Caspase 3 and accelerated Apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H2O2-induced Apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced Apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H2O2-treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H2O2-induced Apoptosis of N2a cells.

Keywords

FOXO1; O-GlcNAcylation; STAT3; apoptosis; oxidative stress.

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