CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Hammitzsch, Ariane; Tallant, C.; Fedorov, O.; O’Mahony, Alison; Brennan, P.E.; Hay, Duncan; Martínez, Fernando O.; Al-Mossawi, Hussein; Wit, Jelle de; Vecellio, Matteo; Wells, Christopher; Wordsworth, P; Müller, Susanne; Knapp, Stefan; Bowness, Paul

doi:10.1073/pnas.1501956112

Cited by 215 publications

(216 citation statements)

References 52 publications

(61 reference statements)

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“…BET inhibitor studies have revealed a growing spectrum of cancers dependent on nonmutated BRD4; thus, identifying the breadth of normal and aberrant BRD4 interactions should provide useful candidates for combined therapeutic approaches. Additional candidates with known inhibitory compounds include XPO1 (6,32), EP300 (33), and the transcriptional elongation complex pTEFb, composed of CDK9 and CCNT1 (34). Interestingly, our study confirms that pTEFb is associated with BRD4-NUT as well as BRD4 (Fig.…”

Section: Discussionsupporting

confidence: 76%

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Alekseyenko

Walsh

Zee

et al. 2017

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

110

167

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To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma (NMC), we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared with wild-type BRD4. Using cross-linking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 associated with BRD4-NUT in NMC patient cells but not detectable in 293T cells. EP300 and ZNF532 are both implicated in feed-forward regulatory loops leading to propagation of the oncogenic chromatin complex in BRD4-NUT patient cells. Adding key functional significance to our biochemical findings, we independently discovered a ZNF532-NUT translocation fusion in a newly diagnosed NMC patient. ChIP sequencing of the major players NUT, ZNF532, BRD4, EP300, and H3K27ac revealed the formation of ZNF532-NUT-associated hyperacetylated megadomains, distinctly localized but otherwise analogous to those found in BRD4-NUT patient cells. Our results support a model in which NMC is dependent on ectopic NUT-mediated interactions between EP300 and components of BRD4 regulatory complexes, leading to a cascade of misregulation.BioTAP-XL | hyperacetylation | ZNF532-NUT | topological domains | BRD4

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Section: Discussionsupporting

confidence: 76%

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Alekseyenko

Walsh

Zee

et al. 2017

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

110

167

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“…80 For example, EP300, which was identified in differential methylated loci in both hyper-and hypo-methylated NK loci, is a bromodomain containing transactivator that has been successfully targeted with small molecule inhibitors. 81 The methylation profile of activated NK cells described here would predict that bromodomain inhibitors targeting EP300 could modulate NK activation, which may be beneficial or undesirable depending on the specific application.…”

Section: Implications For Population-based Research and Therapeuticsmentioning

confidence: 95%

The DNA methylation profile of activated human natural killer cells

et al. 2016

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Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in na€ ıve NK, T-and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.

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“…S6C). This might be due to the fact that bromodomain inhibitors have multiple targets, such as BRD4, which is therapeutically targeted in hematopoietic cancer to downregulate MYC ( 44 ).…”

Section: Research Articlementioning

confidence: 99%

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

Ogiwara¹,

Sasaki²,

Mitachi³

et al. 2016

Cancer Discovery

146

109

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Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifi cally killing CBP-defi cient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP -defi cient cancers identifi ed the CBP paralog p300/EP300 . Ablation of p300 in CBP -knockout and CBP -defi cient cancer cells induced G 1 -S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP -defi cient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifi cally suppressed the growth of CBP -defi cient lung and hematopoietic cancer cells in vitro and in vivo ; thus p300 is a promising therapeutic target for treatment of CBP -defi cient cancers. SIGNIFICANCE:Targeting synthetic-lethal partners of genes mutated in cancer holds great promise for treating patients without activating driver gene alterations. Here, we propose a "synthetic lethalbased therapeutic strategy" for CBP -defi cient cancers by inhibition of the p300 HAT activity. Patients with CBP -defi cient cancers could benefi t from therapy using p300-HAT inhibitors. Cancer Discov; 6(4); 430-45.

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CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses

Cited by 215 publications

References 52 publications

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

Ectopic protein interactions within BRD4–chromatin complexes drive oncogenic megadomain formation in NUT midline carcinoma

The DNA methylation profile of activated human natural killer cells

Targeting p300 Addiction inCBP-Deficient Cancers Causes Synthetic Lethality by Apoptotic Cell Death due to Abrogation ofMYCExpression

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