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

Backe, Marie Balslev LU ; Andersson, Jan Legaard; Bacos, Karl LU ; Christensen, Dan Ploug; Hansen, Jakob Bondo; Dorosz, Jerzy Jòzef; Gajhede, Michael; Dahlby, Tina; Bysani, Madhusudhan LU and Kristensen, Line Hyltoft, et al. (2017) In Molecular and Cellular Endocrinology
Abstract

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... (More)

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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publication status
epub
subject
keywords
Apoptosis, Diabetes, Gene expression, Inflammation, Lysine demethylases, β cells
in
Molecular and Cellular Endocrinology
publisher
Elsevier
external identifiers
  • scopus:85022073768
ISSN
0303-7207
DOI
10.1016/j.mce.2017.07.001
language
English
LU publication?
yes
id
cc39932c-548e-4bc0-839f-dbb8bd0d7e46
date added to LUP
2017-07-24 15:20:35
date last changed
2017-07-25 03:00:02
@article{cc39932c-548e-4bc0-839f-dbb8bd0d7e46,
  abstract     = {<p>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.</p>},
  author       = {Backe, Marie Balslev and Andersson, Jan Legaard and Bacos, Karl and Christensen, Dan Ploug and Hansen, Jakob Bondo and Dorosz, Jerzy Jòzef and Gajhede, Michael and Dahlby, Tina and Bysani, Madhusudhan and Kristensen, Line Hyltoft and Ling, Charlotte and Olsen, Lars and Mandrup-Poulsen, Thomas},
  issn         = {0303-7207},
  keyword      = {Apoptosis,Diabetes,Gene expression,Inflammation,Lysine demethylases,β cells},
  language     = {eng},
  month        = {07},
  publisher    = {Elsevier},
  series       = {Molecular and Cellular Endocrinology},
  title        = {Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function},
  url          = {http://dx.doi.org/10.1016/j.mce.2017.07.001},
  year         = {2017},
}