Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells

• Published in: International journal of molecular sciences 2020-10, Vol.21 (21), p.8016
• Main Authors: Dahlby, Tina, Simon, Christian, Backe, Marie Balslev, Dahllöf, Mattias Salling, Holson, Edward, Wagner, Bridget K, Böni-Schnetzler, Marianne, Marzec, Michal Tomasz, Lundh, Morten, Mandrup-Poulsen, Thomas
• Format: Article
• Language: English
• Subjects: Apoptosis; Cells, Cultured; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Glucose - adverse effects; Humans; Insulin Secretion - drug effects; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Lipids - adverse effects; Signal Transduction; Sweetening Agents - adverse effects
• ISSN: 1422-0067; 1422-0067
• 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.