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

Acta Pharmacologica Sinica volume 45, pages 714–727 (2024)Cite this article

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.

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Fig. 1: H2O2 induces cell apoptosis and decreases O-GlcNAcylation in N2a cells.
Fig. 2: Inhibition of O-GlcNAcylation by OSMI-1 enhances cell apoptosis in N2a cells.
Fig. 3: The total and phosphorylated protein level of STAT3 and FOXO1 in N2A cells were bidirectionally regulated by OSMI-1 or TG.
Fig. 4: The promoter activities of STAT3 and FOXO1 were decreased by OSMI-1, while the promoter activities of STAT3 was increased by OGT overexpression.
Fig. 5: Overexpression of exogenous STAT3 or FOXO1 resists apoptosis induced by OSMI-1.
Fig. 6: The protective effect of thiamet-G (TG) against H2O2-induced apoptosis was alleviated by STAT3 or FOXO1 inhibitors.
Fig. 7: Knockdown of Stat3 or Foxo1 promotes caspase 3 activation and abolishes the protective effect of Thiamet-G against H2O2-induced apoptosis.
Fig. 8: STAT3 and FOXO1 are involved in the protective effect of OGT against H2O2-induced apoptosis.
Fig. 9: O-GlcNAcylation-regulated expression of STAT3 and FOXO1 is involved in H2O2-induced apoptosis in N2a cells.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (32222033 to FFW, 32330041 and 31930046 to LM, 32271064 to CYJ, 32270660 to QML, 32171041 to XL), the Science Technology Innovation 2030 Project of China (2021ZD0203500 to FFW and LM, 2021ZD0202104 to XL, 2022ZD0214500 to CYJ), the CAMS Innovation Fund for Medical Sciences (2021-I2M-5-009 to LM and XL).

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  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

    Chen-chun Zhang, Yuan Li, Chang-you Jiang, Qiu-min Le, Xing Liu, Lan Ma & Fei-fei Wang

  2. Research Unit of Addiction Memory, Chinese Academy of Medical Sciences (2021RU009), Shanghai, 200032, China

    Chen-chun Zhang, Yuan Li, Chang-you Jiang, Qiu-min Le, Xing Liu, Lan Ma & Fei-fei Wang

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Contributions

CCZ designed and performed the experiments. YL, CYJ, QML and XL analyzed the data and provided critical consumables. CCZ drafted the manuscript. LM and FFW supervised the project and revised the manuscript.

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Correspondence to Fei-fei Wang.

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Zhang, Cc., Li, Y., Jiang, Cy. et al. O-GlcNAcylation mediates H2O2-induced apoptosis through regulation of STAT3 and FOXO1. Acta Pharmacol Sin 45, 714–727 (2024). https://doi.org/10.1038/s41401-023-01218-z

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