Stabilization of nuclear β-catenin by inhibiting KDM2A mediates cerebral ischemic tolerance

Authors：Zuo, Yunyan; Zhan, Lixuan; Wen, Haixia; Xue, Jiahui; Tan, Yafu; Sun, Weiwen; Xu, En^*

Source：FASEB Journal, 2023, 37(3): e22796.

DOI：10.1096/fj.202201657

• beta catenin
• brain ischemia
• demethylation
• hippocampus
• neuroprotection

Hypoxic postconditioning (HPC) with 8% oxygen increases nuclear accumulation of beta-catenin through activating the classical Wnt pathway, thereby alleviating transient global cerebral ischemia (tGCI)-induced neuronal damage in the hippocampal CA1 subregion of adult rats. However, little is understood about the regulatory mechanism of nuclear beta-catenin in HPC-mediated cerebral ischemic tolerance. Although lysine(K)-specific demethylase 2A (KDM2A) has been known as a crucial regulator of nuclear beta-catenin destabilization, whether it plays an important role through modulating nuclear beta-catenin in cerebral ischemic tolerance induced by HPC remains unknown. In this study, we explored the molecular mechanism of stabilizing nuclear beta-catenin by inhibiting KDM2A-mediated demethylation in the HPC-offered neuroprotection against tGCI. In addition, we confirmed that nuclear methylated-beta-catenin in CA1 decreased and nuclear beta-catenin turnover increased after tGCI, which were reversed by HPC. The administration with methyltransferase inhibitor AdOx abrogated HPC-induced methylation and stabilization of nuclear beta-catenin in CA1, as well as the neuroprotection against tGCI. Notably, HPC downregulated the expression of KDM2A in CA1 and reduced the interaction between KDM2A and beta-catenin in the nucleus after tGCI. The knockdown of KDM2A with small-interfering RNA could upregulate nuclear methylated-beta-catenin and stabilize beta-catenin, thereby increasing survivin in CA1 and improving the cognitive function of rats after tGCI. Opposite results were observed by the administration of KDM2A-carried adenovirus vector. Furthermore, we demonstrated that KDM2A mediates the demethylation of nuclear beta-catenin through jumonji C (JmjC) domain of KDM2A in HEK-293T and SH-SY5Y cells. Our data support that the inhibition of KDM2A-mediated demethylation of nuclear beta-catenin contributes to HPC-induced neuroprotection against tGCI.

• Institution
  广州医学院; 1