Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in beta-Cells
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- Enhancer of Zeste Homolog 2 (EZH2) Mediates
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Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced beta-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 beta-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. beta-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 (NF kappa B) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NF kappa B 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.
Original language | English |
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Article number | 8016 |
Journal | International Journal of Molecular Sciences |
Volume | 21 |
Issue number | 21 |
Number of pages | 18 |
ISSN | 1661-6596 |
DOIs | |
Publication status | Published - 2020 |
- GLT, histone deacetylases, histone methyltransferase, diabetes, insulin secretion, ER stress, NFκ, B, ENDOPLASMIC-RETICULUM STRESS, LONG-TERM EXPOSURE, HISTONE DEACETYLASES, INSULIN-SECRETION, PANCREATIC-ISLETS, PROTEIN EZH2, INS-1 CELLS, FATTY-ACIDS, INHIBITION, EXPRESSION
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