Histone deacetylases 1 and 3 but not 2 mediate cytokine-induced beta cell apoptosis in INS-1 cells and dispersed primary islets from rats and are differentially regulated in the islets of type 1 diabetic children

Abstract

Aims/hypothesis Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. Methods The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. Results Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the proinflammatory mediators Il1α, Il1β, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. Conclusions/interpretation These data demonstrate nonredundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.

KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response

“…This process involves the antagonistic activity of the chromatin-modifying enzymes lysine/histone deacetylase (KDAC) and lysine/histone acetyl transferase (KAT). Accumulating evidence suggests important roles for KDACs in the control of glucose homeostasis (Mihaylova and Shaw, 2013), notably by regulating endocrine pancreatic development (Haumaitre et al, 2008;Lenoir et al, 2011) and b cell function and survival (Lundh et al, 2012;Plaisance et al, 2014). So far, little is known about the metabolic role of KAT, in particular KAT2B.…”

The lysine deacetylase inhibitor givinostat inhibits β-cell IL-1β induced IL-1β transcription and processing

“…16,17 Here we show that inhibition of KDACs affects the signaling of the cytokines IL-1 and IFNγ individually in the INS-1 cell. Considering the synergistic effects of the combination of these cytokines in the β-cell, this finding illustrates that the protective effects of KDAC inhibition is independent on converging IL-1 and IFNγ signaling.…”

“…Thus, induction of IL-1β and CXCL10 mRNA by IL-1β and IFNγ exposure as well as the inhibitory effects by givinostat are not likely to be explained by effects on histone acetylation. Since we have recently shown that knockdown of HDAC3 reduces NFκB transcriptional activity by reducing p65 DNA binding in β-cells, 17 this could explain the KDACi mediated reduction in proliferation via CXCR3 or Toll-like receptor (TLR) 4 signaling pathways shared with IL-1. 9,10,12 In support of this notion, DNA vaccination-induced CXCL10 antibody production prevented diabetes in NOD mice without altering islet inflammation.…”

“…16,17 Thus, knock down of HDAC1 and 2 significantly inhibits transcription of the directly β cell-toxic inflammatory molecule IL-1β induced by IL-1β and IFNγ in synergy, 17 but it is unknown if KDAC inhibition differentially prevents β-cell transcription of IL-1 induced by single cytokines or processing of IL-1, thereby selectively breaking individual autoinflammatory circuits.…”

Translational implications of the β-cell epigenome in diabetes mellitus

“…Histone deacetylases have been linked with pro-inflammatory effects, and a number of small molecule inhibitors of histone deacetylases (HDACis or KDACis) have been tested in vitro and subsequently applied in preclinical models of T1D and T2D (79, 120, 121). A recent study by Christensen et al tested the effect of the lysine deacetylase inhibitors vorinostat and gininostat in the non-obese diabetic (NOD) model of spontaneous autoimmune-mediated β cell destruction (122).…”