Department of Biomedical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.
Int J Mol Sci. 2020 Oct 29;21(21):8016. doi: 10.3390/ijms21218016.
Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.
选择性抑制组蛋白去乙酰化酶 3（HDAC3）可通过减轻促凋亡内质网（ER）应激信号来预防糖脂毒性诱导的β细胞功能障碍和细胞凋亡，但减轻的精确分子机制尚不清楚。通过对暴露于糖脂毒性的胰岛素分泌细胞的β细胞基因表达谱进行无偏倚的微阵列分析，我们确定 Enhancer of zeste homolog 2（EZH2）为唯一的靶候选物。EZH2 衰减可保护β细胞免受糖脂毒性诱导的 ER 应激和细胞凋亡。EZH2 组蛋白甲基转移酶活性的小分子抑制剂可挽救人胰岛免受糖脂毒性诱导的细胞凋亡。此外，EZH2 敲低细胞可防止糖脂毒性诱导的非经典核因子 kappa 轻多肽基因增强子 B 细胞（NFκB）途径的下调。我们得出结论，EZH2 缺乏可防止糖脂毒性诱导的 ER 应激、细胞凋亡和非经典 NFκB 途径的下调，但不能防止胰岛素分泌功能障碍。该机制可能涉及通过 EZH2 作为甲基转移酶和/或作为依赖于甲基化的转录因子的转录调节。
