The MiR-101/EZH2 negative feedback signaling drives oxygen-glucose deprivation/reperfusion-induced injury by activating the MAPK14 signaling pathway in SH-SY5Y cells.

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MiR-101 has been reported to be involved in neuroinflammation, neuronal injury and neurotoxicity. However, the specific role and mechanism of miR-101 in ischemia/reperfusion (I/R)-induced neuronal injury remain largely unknown. Our study found that after oxygen-glucose deprivation/reperfusion (OGD/R) exposure, the level of miR-101 in SH-SY5Y cells was significantly decreased, which was accompanied by a decrease in cell viability, and an increase in LDH release and apoptosis. MiR-101 overexpression (miR-101 mimics) significantly promoted viability and inhibited LDH release and apoptosis in OGD/R-exposed SH-SY5Y cells. Luciferase reporter assay indicated that enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) was a direct target of miR-101, and EZH2 siRNA obviously increased the viability, inhibited LDH release and apoptosis in OGD/R-exposed SH-SY5Y cells. Besides, EZH2 siRNA could inhibit the activation of mitogen-activatedproteinkinase(MAPK14) signaling pathway and theMAPK14agonist (anisomycin) could reverse EZH2 siRNA-induced increase in cell viability, and decreases in LDH release and apoptosis. Furthermore, when the methyltransferase activity of EZH2 was inhibited by its specific inhibitorGSK126, the level of miR-101 was increased in OGD/R-exposed SH-SY5Y cells. Additionally, EZH2 siRNA upregulated miR-101 expression in OGD/R-exposed SH-SY5Y cells. Taken together, our findings reveal that miR-101/EZH2 negative feedback signaling drives OGD/R-induced injury by activating the MAPK14 signaling pathway in SH-SY5Y cells.