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Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

ABSTRACT: Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

PROVIDER: PRJNA1030521 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26451600_1.fastq.gz	Fastqsanger.gz
	SRR26451600_2.fastq.gz	Fastqsanger.gz
	SRR26451601_1.fastq.gz	Fastqsanger.gz
	SRR26451601_2.fastq.gz	Fastqsanger.gz
	SRR26451602_1.fastq.gz	Fastqsanger.gz

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Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

Project description:Drug-tolerant persister (DTP) cells arise in the early phase of chemotherapy and contribute to tumor relapse. In gastric cancer, we previously identified aldehyde dehydrogenase 1 family member A3 (ALDH1A3) as a DTP signature gene that contributes to survival after chemotherapy, while it remains elusive how the ALDH1A3-overexpressing DTP cells are enriched after chemotherapy and contribute to tumor promotion. Here, we demonstrated that ALDH1A3 was frequently overexpressed in clinical gastric cancer specimen after neoadjuvant chemotherapy and ALDH1A3 overexpression in gastric cancer patient-derived cells (PDCs) promoted tumor growth in vivo. Live imaging revealed that the ALDH1A3-overexpressing DTP cells were induced rather than selected after 5-fluorouracil (5-FU) treatment. We identified global elevation of histone H3 lysine 27 acetylation (H3K27ac) in the promoter regions of DTP cells including ALDH1A3 gene locus. Chemical screening further revealed bromodomain and extra-terminal motif (BET) protein inhibitors as efficient perturbators of the DTP phenotype. The BET inhibitors suppressed 5-FU-induced ADLH1A3 expression and selectively prevented the DTP cell proliferation. Importantly, ALDH1A3 downregulation and growth inhibition by BET inhibitors was rescued by exogenous ALDH1A3 expression. Among BET proteins, BRD4 was preferentially recruited to the ALDH1A3 promoter and promoted its expression in DTP cells. The BET inhibitor, Birabresib/OTX015, significantly suppressed ALDH1A3 expression and potentiated antitumor effect of 5-FU in gastric PDC xenograft model. These data indicate that the global H3K27ac induction and the BRD4-dependent ALDH1A3 induction is essential for gastric cancer drug tolerance.

2023-10-24 | GSE245888 | GEO

Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

2023-10-24 | GSE245887 | GEO

Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

Project description:Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

| PRJNA1030520 | ENA

Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

Project description:Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

| PRJNA1030358 | ENA

BRD4 assists elongation of both coding and enhancer RNAs guided by histone acetylation

Project description:In serum-starved and re-fed mouse fibroblast, nascent RNA-seq analysis showed that the BET inhibitor JQ1 antagonized a process regulating PIC formation and a downstream process involved in progressive elongation. To specifically address the role of BRD4 and its interactions with acetylated histones and P-TEFb, YFP-tagged BRD4 proteins (wild type and mutant BRD4) were stably expressed in cells, endogenous BRD4 of which was knocked down by shRNA (shBRD4). Nascent RNA-seq analysis showed that BRD4 facilitated transcript elongation in a manner dependent on acetylated histone interaction but not P-TEFb. Furthermore, the role of BRD4 in enhancer activity was evaluated by mapping the intergenic distributions of Pol II, CDK9, H3K27 acetylation (Ac) and H4 Ac as well as BRD4 by ChIP-seq analysis. The results suggest that the role of intergenic BRD4 on nearby gene expression is mediated through enhanced synthesis of eRNA.

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CBP/P300 Dependent Histone H3K27 Acetylation

Project description:Enhancer Activity Requires CBP/P300 Bromodomain Dependent Histone H3K27 Acetylation

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Pharmacological targeting of histone H3K27 acetylation/BRD4-dependent induction of ALDH1A3 for early-phase drug tolerance of gastric cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-24 | GSE245889 | GEO

H3K27 acetylation and gene expression during late spermatogenesis

Project description:H3K27 acetylation and gene expression during late spermatogenesis

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Investigation of melanoma cell chromatin acetylation states with high and low levels of ALDH1A3

Project description:Cancer progression and therapy resistance arise from metabolic and transcriptional adaptations, but how these are interconnected is less well understood. We propose that in melanoma, the pan-cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) couples TFAP2B-neural crest stem cell gene transcription with a distinct acetyl-histone H3 landscape via its substrate acetaldehyde. Mechanistically, nuclear acetyl-CoA synthetase 2 (ACSS2) colocalises with ALDH1A3 to bind glucose metabolic and neural crest stem cell gene loci and promote local acetyl-histone H3 modification dependent on ALDH1A3. Consistent with clinical observations that dedifferentiation into stem cell states confer poor prognosis in melanoma patients and mediate drug resistance, we found in a zebrafish melanoma model that targeting the ALDH1A3-high subpopulation with an ALDH1 suicide inhibitor delayed BRAF inhibitor drug-resistant relapse. Our work identifies ALDH1A3 as a master coordinator of acetaldehyde metabolites that directly regulates chromatin-based gene regulation, and which can be pharmacologically targeted to improve therapeutic outcomes.

2024-06-29 | GSE243834 | GEO

H3K27 acetylation and gene expression during late spermatogenesis

Project description:ChIP-seq for H3K27 acetylation and RNA-seq were performed during spermatogenesis. We analyzed two representative stages of spermatogenesis: purified pachytene spermatocytes (PS) undergoing meiosis; and postmeiotic round spermatids (RS) from adult testes.

2018-02-05 | GSE107398 | GEO

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