BET bromodomain inhibitors attenuate transcription of a subset of IL-1-induced NF-κB targets that promote inflammation in β-cells. J Biol Chem 2025 Jul;301(7):110358
Date
06/13/2025Pubmed ID
40505864Pubmed Central ID
PMC12270673DOI
10.1016/j.jbc.2025.110358Scopus ID
2-s2.0-105009466074 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
Cytokine-stimulated transcription of NF-κB target genes is linked to the development of multiple inflammatory and autoimmune diseases. Inhibitors of bromodomain and extraterminal domain (BET) epigenetic reader proteins attenuate inflammatory gene transcription and delay the onset of several inflammatory diseases, including autoimmune diabetes. Our previous studies showed that BET bromodomain inhibitors disrupt the interaction between BET family member BRD4 and NF-κB transcription factor p65 in β-cells, thus attenuating cytokine-stimulated NF-κB-dependent gene and functional changes. However, the role of NF-κB in developing inflammatory disease is controversial, as NF-κB inhibition can promote disease progression in some contexts. NF-κB target genes play both physiological and pathophysiological roles in regulating the cellular response to cytokines. Here, using cytokine-stimulated pancreatic β-cells as an inflammatory disease model, we show that NF-κB-dependent gene products that participate in inflammation are sensitive to BET bromodomain inhibition. In contrast, gene products that maintain cellular homeostasis or protect β-cells from stressors are largely insensitive to BET bromodomain inhibition. These studies define a novel and selective role for BET bromodomain-containing proteins in regulating inflammatory gene activation.
Author List
Nord JA, Makowski SJ, Sidlowski PFW, Bursch KL, Corbett JA, Smith BCAuthors
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinBrian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAzepines
Cell Cycle Proteins
Humans
Inflammation
Insulin-Secreting Cells
Mice
NF-kappa B
Nuclear Proteins
Transcription Factors
Transcription, Genetic
Triazoles
