The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice

Benito, Eva; Ramachandran, Binu; Schroeder, Henning; Schmídt, G.; Urbanke, Hendrik; Burkhardt, Susanne; Capece, Vincenzo; Dean, Camin; Fischer, André

doi:10.1038/tp.2017.202

Cited by 66 publications

(62 citation statements)

References 43 publications

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“…JQ1 treatment almost completely abolished AtT20 cell proliferation and was therefore more efficacious in the AtT20 cells than in pancreatic NET (BON-1) and broncho-pulmonary NET (H727 and H720) cell lines, as reported in our previous studies (Lines et al 2017). Thieno-diazepines similar to JQ1 are currently undergoing clinical trials for a number of different cancers (Matzuk et al 2012, Benito et al 2017 and therefore may have potential as a novel therapeutic compound for corticotrophinomas, although the specific pathways altered by this pan-BET inhibitor, especially in the pituitary, still remain to be fully elucidated (Andrieu et al 2016).…”

Section: Discussionsupporting

confidence: 55%

Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells

Lines

Filippakopoulos

Stevenson

et al. 2020

Endocrine-Related Cancer

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Medical treatments for corticotrophinomas are limited, and we therefore investigated the effects of epigenetic modulators, a new class of anti-tumour drugs, on the murine adrenocorticotropic hormone (ACTH)-secreting corticotrophinoma cell line AtT20. We found that AtT20 cells express members of the bromo and extra-terminal (BET) protein family, which bind acetylated histones, and therefore, studied the anti-proliferative and pro-apoptotic effects of two BET inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, using CellTiter Blue and Caspase Glo assays, respectively. JQ1 and PFI-1 significantly decreased proliferation by 95% (P < 0.0005) and 43% (P < 0.0005), respectively, but only JQ1 significantly increased apoptosis by >50-fold (P < 0.0005), when compared to untreated control cells. The anti-proliferative effects of JQ1 and PFI-1 remained for 96 h after removal of the respective compound. JQ1, but not PFI-1, affected the cell cycle, as assessed by propidium iodide staining and flow cytometry, and resulted in a higher number of AtT20 cells in the sub G1 phase. RNA-sequence analysis, which was confirmed by qRT-PCR and Western blot analyses, revealed that JQ1 treatment significantly altered expression of genes involved in apoptosis, such as NFκB, and the somatostatin receptor 2 (SSTR2) anti-proliferative signalling pathway, including SSTR2. JQ1 treatment also significantly reduced transcription and protein expression of the ACTH precursor pro-opiomelanocortin (POMC) and ACTH secretion by AtT20 cells. Thus, JQ1 treatment has anti-proliferative and pro-apoptotic effects on AtT20 cells and reduces ACTH secretion, thereby indicating that BET inhibition may provide a novel approach for treatment of corticotrophinomas.

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Section: Discussionsupporting

confidence: 55%

Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells

Lines

Filippakopoulos

Stevenson

et al. 2020

Endocrine-Related Cancer

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“…For instance, Brd4 has been reported to modulate pathological cardiac remodeling, and its inhibitor has potential for the treatment of heart failure ( Spiltoir et al, 2013 ). Brd4 has also been shown to be involved in memory function and age-related memory impairment, making it a suitable target to treat neurodegenerative disease ( Magistri et al, 2016 ; Benito et al, 2017 ). Furthermore, Brd4 inhibition has been shown to reduce blood–brain barrier damage and stroke volume, improving sensory and motor function after stroke ( Demars et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Xiang

Lin

et al. 2020

Front. Cell. Neurosci.

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Spinal cord injury (SCI) is a destructive neurological disorder that is characterized by impaired sensory and motor function. Inhibition of bromodomain protein 4 (Brd4) has been shown to promote the maintenance of cell homeostasis by activating autophagy. However, the role of Brd4 inhibition in SCI and the underlying mechanisms are poorly understood. Thus, the goal of the present study was to evaluate the effects of sustained Brd4 inhibition using the bromodomain and extraterminal domain (BET) inhibitor JQ1 on the regulation of apoptosis, oxidative stress and autophagy in a mouse model of SCI. First, we observed that Brd4 expression at the lesion sites of mouse spinal cords increased after SCI. Treatment with JQ1 significantly decreased the expression of Brd4 and improved functional recovery for up to 28 day after SCI. In addition, JQ1-mediated inhibition of Brd4 reduced oxidative stress and inhibited the expression of apoptotic proteins to promote neural survival. Our results also revealed that JQ1 treatment activated autophagy and restored autophagic flux, while the positive effects of JQ1 were abrogated by autophagy inhibitor 3-MA intervention, indicating that autophagy plays a crucial role in therapeutic effects Brd4 induced by inhibition of the functional recovery SCI. In the mechanistic analysis, we observed that modulation of the AMPK-mTOR-ULK1 pathway is involved in the activation of autophagy mediated by Brd4 inhibition. Taken together, the results of our investigation provides compelling evidence that Brd4 inhibition by JQ1 promotes functional recovery after SCI and that Brd4 may serve as a potential target for SCI treatment.

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“…Note also that three of the top five HPC signature proteins (PKP2, PRKCG, MOBP, CORO7, SHISA6), are connected with both BRD4 and BMPR2 pathways. Interestingly, BRD4 is involved in transcriptional regulation of learning and memory, and is expressed in neurons throughout the brain [55,56]. BMPR2 is expressed in HPC and is implicated in the regulation of anxiety-like behaviors in rodents [57][58][59][60].…”

Section: Resultsmentioning

confidence: 99%

Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

Funk

Labilloy

Reigle

et al. 2020

Preprint

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Running title -PSD-95 protein-protein interactions in human brainThe overarching goal of this exploratory study is to link subcellular microdomain specific protein-protein interactomes with big data analytics. We isolated postsynaptic density-95 (PSD-95) complexes from four human brain regions and compared their protein interactomes using multiple bioinformatics techniques. We demonstrate that human brain regions have unique postsynaptic protein signatures that may be used to interrogate perturbagen databases. Assessment of our hippocampal signature using the iLINCS database yielded several compounds with recently characterized "off target" effects on protein-protein interactions in the posynaptic density compartment. Acknowledgments:We would like to thank all those that have supported this research: the L.I.F.E. Foundation, UCNI pilot award, Lindsay Brinkmeyer Schizophrenia Research Fund, Center for Clinical and Translational Science Training (CCTST), and NIH grant MH107916. The MS data was acquired in the University of Cincinnati Proteomics Laboratory on a mass spectrometer funded in part through the NIH S10 shared instrumentation grant RR027015.Altering the expression of PSD-95 protein significantly changes synaptic structure and function, including molecular correlates of learning and memory, long-term potentiation (LTP) and long-term depression (LTD). For example, PSD-95 overexpression increases the amplitude of excitatory postsynaptic currents (EPSCs), to the extent that additional stimulus is unable to further strengthen LTP [13][14][15][16][17]. In contrast, PSD-95 knockdown disrupts postsynaptic density structure and suppresses EPSCs, consistent with a role for PSD-95 in synaptic fidelity [18][19][20]. Further highlighting the importance of PSD-95 in the synapse, knockout of PSD-95 in mice and genomic variants within postsynaptic density hub proteins are particularly implicated in neuropsychiatric disorders such as schizophrenia and autism [21,22].To investigate excitatory postsynaptic protein hubs, we targeted PSD-95 due to its high level of localization to the postsynaptic density (~95%), its well-characterized role as a hub protein, and the large number of constituents in its protein interactome (~1000) [23][24][25]. We designed a series of experiments to examine brain region-specific excitatory postsynaptic proteomes to answer the following questions. 1) Do postsynaptic protein-protein interactions differ by brain region? 2) Can we accurately detect and separate samples based on these differences? and 3) Can region-specific protein interactomes inform functional differences? For these experiments we used four human brain regions (anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus (HPC), and superior temporal gyrus (STG)) from 3 well-matched control male subjects from the Alabama Brain Collection. A total of 289 proteins were identified as part of a PSD-95 protein interactome that were present across all four brain regions.We hypothesize that there is region-specific ...

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The BET/BRD inhibitor JQ1 improves brain plasticity in WT and APP mice

Cited by 66 publications

References 43 publications

Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells

Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells

Inhibition of Brd4 by JQ1 Promotes Functional Recovery From Spinal Cord Injury by Activating Autophagy

Region-Specific PSD-95 Interactomes Contribute to Functional Diversity of Excitatory Synapses in Human Brain

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