HDAC1 interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression

Cartwright, Tyrell N.; Worrell, Julie C.; Marchetti, Letizia; Dowling, Catríona M.; Knox, Amber; Kiely, Patrick A.; Mann, Jelena; Mann, Derek A.; Wilson, Caroline

doi:10.1016/j.bbagrm.2018.09.001

Cited by 20 publications

(8 citation statements)

References 20 publications

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“…The nfkb1 2/2 mouse lacks the p50 subunit of NF-kB, which classically heterodimerizes with RelA to positively regulate inflammatory gene transcription (11). Conversely, p50 homodimers combine with histone deacetylase 1 (HDAC1) to repress inflammatory gene expression (12,13). Hence, p50 homodimers are emerging as key anti-inflammatory signaling factors.…”

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confidence: 99%

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis

Bianchi

Marchetti

Hall

et al. 2021

The Journal of Immunology

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Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1 2/2 mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD + , this leading to increased hepatic NAD + and elevated activity of the NAD +-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-kB (p65), and PGC-1a. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease.

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confidence: 99%

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis

Bianchi

Marchetti

Hall

et al. 2021

The Journal of Immunology

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“…Whereas most of the NF-κB members can form active transcription factors, NFKB1 p50 subunit lacks transactivation domain and p50:p50 homodimers have been shown to act as stimulus-specific repressors notably during the resolution phase of inflammation, by recruiting H3K9 methyltransferases and HDAC at both NF-κB and type-I interferon (IFN) response genes (Elsharkawy et al, 2010; Ea et al, 2012; Cartwright et al, 2018). p50:p65 heterodimers are the most abundant form of NF-κB generated upon inflammatory stimuli.…”

Section: Discussionmentioning

confidence: 99%

The NF-κB pathway controls H3K9me3 levels at intronic LINE-1 elements and hematopoietic stem cell gene expression in cis

Pelinski

Hidaoui

Hermetet

et al. 2021

Preprint

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Understanding how ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long-term is crucial. We recently showed a link between derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements, and IR-induced HSC injury. L1 contribute to gene regulatory networks. However, the mechanisms involved in IR-induced L1Md derepression, and their impact on HSC transcriptome remain to be addressed. Here we show that IR triggers genome-wide H3K9me3 decreased and transcriptomic changes in HSCs, characterized by a loss of the TNF-α/NF-κB and HSC signatures. HSC gene repression is associated to H3K9me3 loss at specific intronic L1Md displaying NF-κB binding sites. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment before IR rescued all these effects and prevented IR-induced HSC loss of function in vivo. This reveals the importance of the TNF-α/NF-κB pathway to control H3K9me3 levels at selected intronic L1Md and thereby preserve HSC gene expression and function during IR stress.

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ All mice were killed by cervical dislocation. After removing red blood cells using Quicklysis solution (Cytognos SL; Salamanca, Spain), neutrophils were isolated and purified following the Neutrophil Isolation Kit protocol (Miltenyi Biotec; Bergisch Gladbach, Germany [reference # 130-097-658]) [17][18][19] . The degree of the neutrophil purity achieved (CD11b + Ly6G+ cells; Table S3 in Supplementary Material) was assessed using standard sorting procedures by flow cytometry.…”

Section: Experiments For Neutrophil Phenotype Characterization Isolamentioning

confidence: 99%

Effects of anti-PD-1 immunotherapy on tumor regression: insights from a patient-derived xenograft model

Martín-Ruiz

Fiuza‐Luces

Martínez-Martínez

et al. 2020

Sci Rep

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Immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), have resulted in unprecedented improvements in survival for patients with lung cancer. Nonetheless, not all patients benefit equally and many issues remain unresolved, including the mechanisms of action and the possible effector function of immune cells from non-lymphoid lineages. The purpose of this study was to investigate whether anti-PD-1 immunotherapy acts on malignant tumor cells through mechanisms beyond those related to T lymphocyte involvement. We used a murine patientderived xenograft (PDX) model of early-stage non-small cell lung carcinoma (NSCLC) devoid of host lymphoid cells, and studied the tumor and immune non-lymphoid responses to immunotherapy with anti-PD-1 alone or in combination with standard chemotherapy (cisplatin). An antitumor effect was observed in animals that received anti-PD-1 treatment, alone or in combination with cisplatin, likely due to a mechanism independent of T lymphocytes. Indeed, anti-PD-1 treatment induced myeloid cell mobilization to the tumor concomitant with the production of exudates compatible with an acute inflammatory reaction mediated by murine polymorphonuclear leukocytes, specifically neutrophils. Thus, while keeping in mind that more research is needed to corroborate our findings, we report preliminary evidence for a previously undescribed immunotherapy mechanism in this model, suggesting a potential cytotoxic action of neutrophils as PD-1 inhibitor effector cells responsible for tumor regression by necrotic extension. Cancer immunotherapy, in particular antibody-based immune checkpoint blockers, represents a revolution in cancer treatment, generating unprecedented results in terms of overall and progression-free survival 1,2. Several of the most studied immune checkpoint targets, such as programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1 axis), are involved in escape mechanisms from immunosurveillance 2-4. Accordingly, anti-PD-1 therapies (e.g., nivolumab) are based on improving the anti-tumor immune response against cancer cells, principally by stimulating the infiltrating cytotoxic T lymphocytes (CD8+) in the tumor microenvironment 5-7. These therapies block the immunoinhibitory receptor PD-1, which is normally expressed on the surface of activated T cells, regulatory T cells, B cells and natural killer (NK) cells 3,6,7. However, in addition to low objective response rate for some tumors, notably for non-small cell lung carcinoma (NSCLC) and nivolumab 8,9 , there is a wide inter-individual variability of response to anti-PD-1 therapy, which complicates the task of reliably identifying responders and non-responders. Moreover, there are no robust markers to predict which patients are most likely to benefit from this therapy 10. Indeed, the determination

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HDAC1 interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression

Abstract: interacts with the p50 NF-κB subunit via its nuclear localization sequence to constrain inflammatory gene expression. Biochimica et Biophysica Acta:

Cited by 20 publications

References 20 publications

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis

The NF-κB pathway controls H3K9me3 levels at intronic LINE-1 elements and hematopoietic stem cell gene expression in cis

Effects of anti-PD-1 immunotherapy on tumor regression: insights from a patient-derived xenograft model

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