BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Nicholas, Dequina; Andrieu, Guillaume P.; Strissel, Katherine J.; Nikolajczyk, Barbara S.; Denis, Gerald V.

doi:10.1007/s00018-016-2320-0

Cited by 24 publications

(16 citation statements)

References 173 publications

(209 reference statements)

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“…Small molecules targeting BET family proteins possess an antiinflammatory effect (31,32). However, these inhibitors target all BET family proteins, including Brd2, Brd3, and Brd4.…”

Section: Discussionmentioning

confidence: 99%

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Bao

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/ threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.T he inducible transcription factor NF-κB plays a key role in regulating the inflammatory and immune responses in mammals (1, 2). The prototypical NF-κB complex, the heterodimer of p50 and RelA, is sequestered in the cytoplasm by its assembly with its inhibitor IκBα (1, 2). Upon stimulation, IκB kinase complex is activated and phosphorylates IκBα, leading to the degradation of IκBα, the nuclear translocation of NF-κB complex, and the activation of NF-κB target genes (1-3). Importantly, one of NF-κB target genes is its inhibitor, IκBα. The resynthesized IκBα enters the nucleus, where it removes the NF-κB from the DNA and terminates activated NF-κB (1, 2, 4). The resynthesis of IκBα therefore creates a negative feedback regulation of NF-κB signaling, preventing sustained NF-κB activation and prolonged inflammatory response.In addition to the negative feedback regulation from resynthesized IκBα, the NF-κB-mediated inflammatory response is subjected to many layers of regulation, including transcriptional, translational, and posttranslational regulation (5-8). Recent studies demonstrate that selective translational control of gene expression plays an important regulatory role in the inflammatory response (7, 9). The eukaryotic translation initiation factor eIF4E has been shown to be the node of the translational control of immune response via the mTOR signaling pathway or the MAPK-Mnk1-Mnk2-eIF4E pathway (9). Upon LPS stimulation, eIF4E can be activated via its phosphorylation at S209 by Mnk1/2 (10). The phosphorylated eIF4E then activates the translation of mRNA of inflammatory genes, including IRF8 (11, 12). Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of e...

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“…Small molecules targeting BET family proteins possess an antiinflammatory effect (31,32). However, these inhibitors target all BET family proteins, including Brd2, Brd3, and Brd4.…”

Section: Discussionmentioning

confidence: 99%

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Bao

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…A growing body of evidence indicates that epigenetic control mechanisms are involved in regulating the immune system. Recent studies confirmed that BET proteins may affect the progression of inflammation and demonstrated that they are critical for macrophage activation [35,[77][78][79][80]. Brd2 and Brd4 physically associate with the promoters of inflammatory cytokine genes, reducing production of cytokines TNFα, IL-6, MCP-1 in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 91%

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

Czapski

Zhao

Lukiw

et al. 2020

IJMS

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Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer’s disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis.

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“…At present, many studies have found that diabetes not only increases the incidence of breast cancer [ 12 ], liver cancer [ 13 ], and lung cancer [ 14 ], but also affects the prognosis of pancreatic cancer [ 15 , 16 ], colon cancer [ 17 , 18 ] and other cancers [ 19 , 20 ], which are in agreement with our study. There are several potential explanations for the observed association between DM and higher risk of mortality in patients with cancers such as colorectal [ 21 – 23 ] and breast [ 24 , 25 ] cancers. Hyperglycemia promotes tumor growth and neoplastic proliferation [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Type 2 Diabetic Mellitus Is a Risk Factor for Nasopharyngeal Carcinoma: A 1:2 Matched Case–Control Study

Peng¹,

Xie²,

Qiu³

et al. 2016

PLoS ONE

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BackgroundDiabetes has been identified as an adverse prognostic variable which associated with an increased mortality in various cancers, including colorectal, lung, and breast cancers. However, previous studies provided inconsistent results on the association between diabetes and nasopharyngeal carcinoma (NPC). The main aim of this study was to investigate the associations between diabetes mellitus and the survival of NPC patients.MethodsThis study was designed as a 1:2 matched case–control study. Cases were patients who met the criteria for the diagnosis of type 2 diabetic mellitus (DM) below. Controls, matched 1:2, were patients who were normoglycemic (NDM). The survival rates were assessed by Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model.ResultsBoth locoregional relapse-free survival (LRRFS) and disease-free survival (DFS) in the NDM group were higher than that in the DM group (p = 0.001 and p = 0.033). Additionally, subset analyses revealed that the differences in OS, LRRFS, and DFS were all significant between the two groups in the N0-N1 subset (p = 0.007, p =.000 and p = 0.002). The LRRFS was higher in the NDM group in the III-IV, T3-T4 and N0-N1 subsets (p = 0.004, p = 0.002 and p =.000). In T3-T4 subset, the NDM group experienced higher DFS than the DM group (p = 0.039). In multivariate analysis, T stage and N stage were found to be independent predictors for OS, DMFS and DFS; chemotherapy was a significant prognostic factor for DMFS and DFS, age for OS, and diabetes for LRRFS and DFS.ConclusionsType 2 diabetic mellitus is associated with poorer prognosis among patients with NPC.

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BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Cited by 24 publications

References 173 publications

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

Type 2 Diabetic Mellitus Is a Risk Factor for Nasopharyngeal Carcinoma: A 1:2 Matched Case–Control Study

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