Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

Publication date: Available online 4 July 2017
Source:Molecular and Cellular Endocrinology
Author(s): Marie Balslev Backe, Jan Legaard Andersson, Karl Bacos, Dan Ploug Christensen, Jakob Bondo Hansen, Jerzy Jòzef Dorosz, Michael Gajhede, Tina Dahlby, Madhusudhan Bysani, Line Hyltoft Kristensen, Charlotte Ling, Lars Olsen, Thomas Mandrup-Poulsen
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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