Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function
2017
Backe, Marie Balslev | Andersson, Jan Legaard | Bacos, Karl | Christensen, Dan Ploug | Hansen, Jakob Bondo | Dorosz, Jerzy Jòzef | Gajhede, Michael | Dahlby, Tina | Bysani, Madhusudhan | Kristensen, Line Hyltoft | Ling, Charlotte | Olsen, Lars | Mandrup-Poulsen, Thomas
Transcriptional changes control β-cell survival in response to inflammatory stress. Posttranslational modifications of histone and non-histone transcriptional regulators activate or repress gene transcription, but the link to cell-fate signaling is unclear. Inhibition of lysine deacetylases (KDACs) protects β cells from cytokine-induced apoptosis and reduces type 1 diabetes incidence in animals. We hypothesized that also lysine demethylases (KDMs) regulate β-cell fate in response to inflammatory stress.Expression of the demethylase Kdm6B was upregulated by proinflammatory cytokines suggesting a possible role in inflammation-induced β-cell destruction. Inhibition of KDM6 demethylases using the selective inhibitor GSK-J4 protected insulin-producing cells and human and mouse islets from cytokine-induced apoptosis by blunting nuclear factor (NF)-κB signaling and endoplasmic reticulum (ER) stress response gene expression. GSK-J4 furthermore increased expression of insulin gene and glucose-stimulated insulin secretion. Expression of genes regulating purinergic and cytokine ligand-receptor interactions was downregulated following GSK-J4 exposure, while expression of genes involved in cell maintenance and survival was upregulated. These data suggest that KDMs are important regulators of inflammation-induced β-cell dysfunction and death.
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