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CBP/p300 HAT maintains the gene network critical for β cell identity and functional maturity.

ABSTRACT: Loss of β cell identity and functional immaturity are thought to be involved in β cell failure in type 2 diabetes. CREB-binding protein (CBP) and its paralogue p300 act as multifunctional transcriptional co-activators and histone acetyltransferases (HAT) with extensive biological functions. However, whether the regulatory role of CBP/p300 in islet β cell function depends on the HAT activity remains uncertain. In this current study, A-485, a selective inhibitor of CBP/p300 HAT activity, greatly impaired glucose-stimulated insulin secretion from rat islets in vitro and in vivo. RNA-sequencing analysis showed a comprehensive downregulation of β cell and α cell identity genes in A-485-treated islets, without upregulation of dedifferentiation markers and derepression of disallowed genes. A-485 treatment decreased the expressions of genes involved in glucose sensing, not in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. In the islets of prediabetic db/db mice, CBP/p300 displayed a significant decrease with key genes for β cell function. The deacetylation of histone H3K27 as well as the transcription factors Hnf1α and Foxo1 was involved in CBP/p300 HAT inactivation-repressed expressions of β cell identity and functional genes. These findings highlight the dominant role of CBP/p300 HAT in the maintenance of β cell identity by governing transcription network.

SUBMITTER: Zhang L

PROVIDER: S-EPMC8116341 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Therapeutic targeting of p300/CBP HAT domain for the treatment of NUT midline carcinoma.

Project description:Nuclear protein of the testis (NUT) midline carcinoma (NMC), is a rare and highly aggressive form of undifferentiated squamous cell carcinoma. NMC is molecularly characterized by chromosomal rearrangement of the NUT gene to another gene, most commonly the bromodomain and extraterminal domain (BET) gene BRD4, forming the BRD4-NUT fusion oncogene. Therefore, inhibiting BRD4-NUT oncogenic function directly by BET inhibitors represents an attractive therapeutic approach but toxicity may limit the use of pan-BET inhibitors treating this cancer. We thus performed a drug screening approach using a library consisting of epigenetic compounds and 'Donated Chemical Probes' collated by the Structural Genomics Consortium (SGC) and identified the p300/CBP HAT inhibitor A-485, in addition to the well-known BET inhibitor JQ1, to be the most active candidate for NMC treatment. In contrast to JQ1, A-485 was selectively potent in NMC compared to other cell lines tested. Mechanistically, A-485 inhibited p300-mediated histone acetylation, leading to disruption of BRD4-NUT binding to hyperacetylated megadomains. Consistently, BRD4-NUT megadomain-associated genes MYC, CCAT1 and TP63 were downregulated by A-485. A-485 strongly induced squamous differentiation, cell cycle arrest and apoptosis. Combined inhibition of p300/CBP and BET showed synergistic effects. In summary, we identified the p300/CBP HAT domain as a putative therapeutic target in highly therapy-resistant NMC.

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Project description:Increasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature β cells in mice. Rfx6 loss in adult β cells leads to glucose intolerance, impaired β cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca(2+) channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of "disallowed" genes, a group usually specifically repressed in adult β cells, and thus to the maintenance of β cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to β cell failure in humans.

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Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis.

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p300/CBP

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

| PRJEB41478 | ENA

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Project description:Drug target P300/CBP in mCRPC

| PRJEB41497 | ENA

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