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HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

ABSTRACT: HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

PROVIDER: PRJNA904707 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22390511_1.fastq.gz	Fastqsanger.gz
	SRR22390511_2.fastq.gz	Fastqsanger.gz
	SRR22390512_1.fastq.gz	Fastqsanger.gz
	SRR22390512_2.fastq.gz	Fastqsanger.gz
	SRR22390513_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis

Project description:Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a gene expression signature associated with a neural crest-stem cell like state (NCSC) and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion, resistance to stress and the development of MBM. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development.

2023-09-26 | PXD044471 | Pride

HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

Project description:Stress-induced HDAC8 activity has been determined to be a driver of a neural crest stem cell (NCSC)-like transcriptional state that increased the formation of melanoma brain metastases (MBM). RNA-Seq experiments were performed against forced HDAC8 expressing cells and empty vector containing melanoma cells to determine differences in gene expression for the HDAC8-induced NCSC-like transcriptional state.

2023-09-26 | GSE218625 | GEO

Project description:HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

| PRJNA903203 | ENA

HDAC8 mediated alterations in melanoma cell line gene expression

Project description:HDAC8 expression is causative for resistance to BRAF inhibiton and increased migration in BRAF mutant melanoma cell lines. Changes in gene expression were determined upon forced HDAC8 expression in an isogenic cell line.

2023-09-26 | GSE240307 | GEO

Lesion-dependent Hdac8 interactome

Project description:In this project anti-Hdac8 immunoaffinity purifications (IPs) of nerves isolated from WT and Hdac8 knock out mice were compared. Nerves were either crushed prior IP (lesion, CR) or not (no lesion, CO). IPs were performed 1 dpL. In total four IPs were performed.

2024-12-02 | PXD046582 | Pride

EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer

Project description:Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5, also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis.

2023-10-24 | PXD039998 | Pride

Gene expression in HDAC8 and HDAC9 silencing keratinocyte

Project description:In this study, we analyzed inflammatory response to Poly:IC under HDAC8 or HDAC9 silencing keratinocyte and performed pathway analysis by RNA-seq.

2020-07-11 | GSE154163 | GEO

Effect of mutation at the K202 site of the HDAC8 on 3D genomic structure in HeLa cells

Project description:HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.

2024-05-24 | GSE247609 | GEO

Overexpression of HDAC8 establishes a unique gene signature in BRAF-mutant melanoma cells

Project description:Systems level analyses using mass spectrometry-based phosphoproteomics and RNA-Seq implicated HDAC8 in the regulation of MAPK and AP-1 signaling pathways. Introduction of HDAC8 into drug-naïve melanoma cells conveyed resistance both in vitro and in in vivo xenograft models. HDAC8-mediated BRAF inhibitor resistance was mediated via receptor tyrosine kinase (RTK) activation leading to Ras/CRAF/MEK/ERK signaling. Although HDACs primarily function at the histone level, they also regulate signaling through the modulation of non-histone substrates. In line with this, HDAC8 introduction decreased the acetylation of c-Jun, increasing its transcriptional activity and enriching for an AP-1 gene signature. Mutation of the putative c-Jun acetylation site at lysine residue 273 reduced the transcriptional activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition through increased RTK expression and enhanced MAPK pathway activity.

2019-04-15 | GSE127564 | GEO

Effect of mutation at the K202 site of the HDAC8 on gene expression in HeLa cells

Project description:HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal acetylated K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, negatively modulates HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation negatively impacts cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings illuminate the reversible acetylation of HDAC8 as a novel cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.

2024-05-24 | GSE247610 | GEO

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