Stabilization of nuclear β‐catenin by inhibiting KDM2A mediates cerebral ischemic tolerance. Issue 3 (1st February 2023)

• Record Type: Journal Article
• Authors: Zuo, Yunyan; Zhan, Lixuan; Wen, Haixia; Xue, Jiahui; Tan, Yafu; Sun, Weiwen; Xu, En
• Is Part Of: FASEB journal. Volume 37:Issue 3(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-01
• Subjects: beta catenin -- brain ischemia -- demethylation -- hippocampus -- neuroprotection; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202201657
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Hypoxic postconditioning (HPC) with 8% oxygen increases nuclear accumulation of β‐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 β‐catenin in HPC‐mediated cerebral ischemic tolerance. Although lysine(K)‐specific demethylase 2A (KDM2A) has been known as a crucial regulator of nuclear β‐catenin destabilization, whether it plays an important role through modulating nuclear β‐catenin in cerebral ischemic tolerance induced by HPC remains unknown. In this study, we explored the molecular mechanism of stabilizing nuclear β‐catenin by inhibiting KDM2A‐mediated demethylation in the HPC‐offered neuroprotection against tGCI. In addition, we confirmed that nuclear methylated‐β‐catenin in CA1 decreased and nuclear β‐catenin turnover increased after tGCI, which were reversed by HPC. The administration with methyltransferase inhibitor AdOx abrogated HPC‐induced methylation and stabilization of nuclear β‐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 β‐catenin in the nucleus after tGCI. The knockdown of KDM2A with small‐interfering RNA could upregulate nuclear methylated‐β‐catenin and stabilize β‐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 β‐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 β‐catenin contributes to HPC‐induced neuroprotection against tGCI.