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Apoptosis plays an important role in neural development and neurological disorders. In this study, we found that O-GlcNAcylation, a unique protein posttranslational modification with O-linked β-N-acetylglucosamine (GlcNAc), promoted apoptosis through attenuating phosphorylation/activation of AKT and Bad. By using co-immunoprecipitation and mutagenesis techniques, we identified O-GlcNAc modification at both Thr308 and Ser473 of AKT. O-GlcNAcylation-induced apoptosis was attenuated by over-expression of AKT. We also found a dynamic elevation of protein O-GlcNAcylation during the first four hours of cerebral ischemia, followed by continuous decline after middle cerebral artery occlusion (MCAO) in the mouse brain. The elevation of O-GlcNAcylation coincided with activation of cell apoptosis. Finally, we found a negative correlation between AKT phosphorylation and O-GlcNAcylation in ischemic brain tissue. These results indicate that cerebral ischemia induces a rapid increase of O-GlcNAcylation that promotes apoptosis through down-regulation of AKT activity. These findings provide a novel mechanism through which O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.

The silent information regulation factor 1 (sirtuin Type 1, SIRT1), as a kind of NAD+ dependent class III histone deacetylation enzyme, has been found to be involved in tumor proliferation, invasion, and metastasis. The roles of SIRTl in breast cancer is multifaceted depending on its substrate from upstream or downstream signaling pathway. In this study, we sought to make clear the regulating effects of SIRT1 in breast cancer cells, and to explore the underlying mechanisms through which SIRT1 regulates breast cancer. First, our results showed that SIRT1 was significantly up-regulated in breast cancer tissues and cells, which correlated with histological grade, tumor size, as well as lymph node metastasis. Then we established SIRT1-overexpressed and SIRT1- knockdown breast cancer cell lines to investigate the functions of SIRT1 in regulating colony formation, cell proliferation, cell cycle, cell apoptosis and migration. We found that overexpression of SIRT1 significantly promoted breast cancer growth both in vitro and in vivo, whereas knockdown of SIRT1 inhibited these phenotypes. Furthermore, SIRT1 was found to interact with Akt directly, consequently promoting the activity of Akt in breast cancer cells in vitro and positively correlating with expression of Akt, P-Akt, in breast cancer tissues in vivo. Down regulation the activity of Akt partially weakened the proliferative effect mediated by SIRT1. Taken together, our results demonstrated SIRT1's tumor promotion function and potential mechanisms in breast cancer, thus providing valuable therapeutic targets for breast cancer.