Bromodomain inhibitor JQ1 reversibly blocks IFN-γ production

Gibbons, Hunter R.; Mi, Deborah J.; Farley, Virginia M.; Esmond, Tashawna; Kaood, Mary B.; Aune, Thomas M.

doi:10.1038/s41598-019-46516-x

Cited by 45 publications

(37 citation statements)

References 48 publications

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“…Overall, these data indicate that DM2 + CVD monocytes are hyperactivated by the pro-M1 stimulant IFNγ, leading to an enhanced expression of chemokines and genes within the NF-κB pathway. Previous reports have indicated that IFNγ signalling is sensitive to BET inhibition [25,45,48,49]. Ex vivo treatment with apabetalone suppressed the transcription of genes that responded differentially to IFNγ, namely CCL8, TNF, RELA, MYD88, CCL7 and IFITM1 (Fig.…”

Section: Apabetalone Counters Dm2 + Cvd Monocyte Hyper-responsivenessmentioning

confidence: 73%

BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

et al. 2020

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Background Patients with cardiovascular disease (CVD) and type 2 diabetes (DM2) have a high residual risk for experiencing a major adverse cardiac event. Dysregulation of epigenetic mechanisms of gene transcription in innate immune cells contributes to CVD development but is currently not targeted by therapies. Apabetalone (RVX-208) is a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins—histone acetylation readers that drive pro-inflammatory and pro-atherosclerotic gene transcription. Here, we assess the impact of apabetalone on ex vivo inflammatory responses of monocytes from DM2 + CVD patients. Results Monocytes isolated from DM2 + CVD patients and matched controls were treated ex vivo with apabetalone, interferon γ (IFNγ), IFNγ + apabetalone or vehicle and phenotyped for gene expression and protein secretion. Unstimulated DM2 + CVD monocytes had higher baseline IL-1α, IL-1β and IL-8 cytokine gene expression and Toll-like receptor (TLR) 2 surface abundance than control monocytes, indicating pro-inflammatory activation. Further, DM2 + CVD monocytes were hyper-responsive to stimulation with IFNγ, upregulating genes within cytokine and NF-κB pathways > 30% more than control monocytes (p < 0.05). Ex vivo apabetalone treatment countered cytokine secretion by DM2 + CVD monocytes at baseline (GROα and IL-8) and during IFNγ stimulation (IL-1β and TNFα). Apabetalone abolished pro-inflammatory hyper-activation by reducing TLR and cytokine gene signatures more robustly in DM2 + CVD versus control monocytes. Conclusions Monocytes isolated from DM2 + CVD patients receiving standard of care therapies are in a hyper-inflammatory state and hyperactive upon IFNγ stimulation. Apabetalone treatment diminishes this pro-inflammatory phenotype, providing mechanistic insight into how BET protein inhibition may reduce CVD risk in DM2 patients.

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Section: Apabetalone Counters Dm2 + Cvd Monocyte Hyper-responsivenessmentioning

confidence: 73%

BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

et al. 2020

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“…Thus, in cell types where AR regulation of ACE2 and TMPRSS2 does not exist, the broader transcriptional repression by BET inhibitors may block expression of these key host factors, and agents targeting BET proteins may have a different therapeutic efficacy in COVID-19 than direct AR inhibitors. BET inhibitors can also affect innate and adaptive immune responses, through processes such as repression of IFNG (IFN gamma) ( 32 ), which could potentially attenuate the cytokine storm associated with COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Targeting transcriptional regulation of SARS-CoV-2 entry factorsACE2andTMPRSS2

Qiao

Wang

Mannan

et al. 2020

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

165

176

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). TMPRSS2 was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of ACE2, TMPRSS2, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.

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“…Importantly, IFN-γ seRNA maintains the interaction of NF-κB with IFN-γ locus, which boosts innate and adaptive immune responses against cancer progression [119]. Preclinical data showed that BET inhibitor JQ1 prominently abrogates BRD4-associated IFN-γ seRNA and IFN-γ production via suppressing RNA Pol II binding to the IFN-γ locus, which results in dysfunction of CD4+ T and NK cells, following by the weak immune response [91].…”

Section: Serna Participates In Immune Responsementioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

Tang

2020

Mol Cancer

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seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA's characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.

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Bromodomain inhibitor JQ1 reversibly blocks IFN-γ production

Cited by 45 publications

References 48 publications

BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

BET protein inhibitor apabetalone (RVX-208) suppresses pro-inflammatory hyper-activation of monocytes from patients with cardiovascular disease and type 2 diabetes

Targeting transcriptional regulation of SARS-CoV-2 entry factorsACE2andTMPRSS2

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

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