TY - JOUR

T1 - Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function

AU - Backe, Marie Balslev

AU - Andersson, Jan Legaard

AU - Bacos, Karl

AU - Christensen, Dan Ploug

AU - Hansen, Jakob Bondo

AU - Dorosz, Jerzy Jòzef

AU - Gajhede, Michael

AU - Dahlby, Tina

AU - Bysani, Madhusudhan

AU - Kristensen, Line Hyltoft

AU - Ling, Charlotte

AU - Olsen, Lars

AU - Mandrup-Poulsen, Thomas

N1 - Copyright © 2017. Published by Elsevier B.V.

PY - 2018/1/15

Y1 - 2018/1/15

N2 - 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.

AB - 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.

KW - Apoptosis

KW - beta cells

KW - Inflammation

KW - Lysine demethylases

KW - Gene expression

KW - Diabetes

U2 - 10.1016/j.mce.2017.07.001

DO - 10.1016/j.mce.2017.07.001

M3 - Journal article

C2 - 28684291

VL - 460

SP - 47

EP - 56

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

ER -