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P300/CBP mediated activation of MHCI machinery and IFNg receptor loci controls chemoimmunotherapy

ABSTRACT: p300/CBP mediated activation of MHCI machinery and IFNg receptor loci controls chemoimmunotherapy

PROVIDER: PRJNA636609 | ENA |

REPOSITORIES: ENA

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p300/CBP mediated activation of MHCI machinery and IFNg receptor loci controls chemoimmunotherapy

Project description:Certain chemotherapeutic drugs potentiate responses to immune checkpoint inhibitors (ICI), including PD-(L)1 antibodies, but the mechanisms underlying this synergism are poorly understood. Many cancers evade immune rejection by suppressing MHC-I antigen processing and presentation (AgPP). We show that two classes of DNA damaging drugs, platinoids (e.g. oxaliplatin) and topoisomerase inhibitors (e.g. mitoxanthrone), induce NF-kB activation, nuclear translocation of the histone and lysine acetyl transferases p300/CBP, interferon (IFN) regulatory factors and IFNg receptor 2 (IFNgR2). This results in transcriptional activation of loci coding for the MHC-I transactivator NLRC5 and components of the MHC-I AgPP machinery. Accordingly, p300 inactivation prevents drug-induced upregulation of MHC-I antigen presentation leading to impaired recognition of cancer cells by effector CD8+ T cells, whose tumor rejecting activity is IFNgR2-dependent. Correspondingly, EP300 loss in human cancers correlates with reduced expression of MHC-I related genes and/or changes in neoantigen amount and expression, suggesting that p300 is an immune-directed oncosuppressor.

2021-02-01 | GSE151611 | GEO

Platinoid drugs augment immunotherapy via histone acetylation of MHCI machinery genes [AT_MC]

Project description:Here we show that low dose Oxali, and to a lesser extent other platinoids, can uniquely activate the transcriptional program that controls MHCI antigen processing and presentation. Activation of this program correlates with induction of histone acetylation and enhanced chromatin accessibility. Oxaliplatin also induces NF-kB dependent IFNg receptor 2 (IFNgR2) thereby augmenting the tumor response to exogenous IFNg produced by reinvigorated effector CD8+ T cells.

2021-02-01 | GSE126287 | GEO

Platinoid drugs augment immunotherapy via histone acetylation of MHCI machinery genes [TRAMP]

2021-02-01 | GSE126273 | GEO

Platinoid drugs augment immunotherapy via histone acetylation of MHCI machinery genes [Myc_CaP]

2021-02-01 | GSE126269 | GEO

Platinoid drugs augment immunotherapy via histone acetylation of MHCI machinery genes [CCO19-MC]

2021-02-01 | GSE126274 | GEO

P300-CBP

Project description:Drug target P300/CBP in mCRPC

| PRJEB41497 | ENA

CBP/p300 transcriptome

Project description:CBP/p300 transcriptome

| PRJNA358160 | ENA

p300/CBP

Project description:Targeting the p300/CBP axis in lethal prostate cancer.

| PRJEB41478 | ENA

CBP/p300 transcriptome

Project description:Comparison of CBP/p300 gene knock-out, bromodomain inhibitor, and acetyltransferase inhibitors Cmpd-R and A-485 in the same cell line (MEF).

2018-06-13 | GSE92613 | GEO

Epigenetic mechanisms to propagate histone acetylation by p300/CBP

Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.

2023-05-08 | PXD040835 | Pride

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