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Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer - organoids

ABSTRACT: Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer - organoids

PROVIDER: PRJEB73608 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR12724804_1.fastq.gz	Fastqsanger.gz
	ERR12724804_2.fastq.gz	Fastqsanger.gz
	ERR12724805_1.fastq.gz	Fastqsanger.gz
	ERR12724805_2.fastq.gz	Fastqsanger.gz
	ERR12724806_1.fastq.gz	Fastqsanger.gz

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Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

Project description:Exploring epigenetic gene essentiality identifying key regulators of cell survival represents a promising way to exploit new targets to overcome resistance to current pharmacological regimens. In breast cancer (BC), endocrine therapy (ET) resistance arises from aberrant Estrogen Receptor alpha (ERα) signaling and targeting cancer cell vulnerability within the ERα pathway represents a rationale for development of effective new drugs against this disease. By combining bioinformatics analysis of genome-wide ‘drop-out’ screenings and siRNA-mediated gene knock-down (kd) we identified a set of essential genes that includes, as the most effective, the bromodomain containing protein BRPF1. BRPF1 belongs to a family of epigenetic readers acting as chromatin remodelers to control gene transcription. To gather mechanistic insight into the role of this epienzyme in BC, we applied chromatin and transcriptome profiling, gene ablation and specific pharmacological inhibition followed by cellular and functional assays. Experimental evidences indicate that BRPF1 associates with ERa in MCF-7 cells chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through modulation of chromatin accessibility. This results in a widespread inhibition of ER-dependent hormonal signaling obtained by ERa gene silencing in AE-sensitive and -resistant BC cells and pre-clinical patient-derived models (PDO). The characterization of functional interplays between ERα and BRPF1 revealed a new master regulator of BC survival, providing a rationale for a BRPF1 targeted cancer diagnosis and highlighting a new therapeutic vulnerability for the treatment of these aggressive tumors.

2024-10-03 | E-MTAB-13884 | biostudies-arrayexpress

Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

2024-10-03 | E-MTAB-13885 | biostudies-arrayexpress

Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

2024-10-03 | E-MTAB-13876 | biostudies-arrayexpress

Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer - organoids

2024-10-04 | E-MTAB-13887 | biostudies-arrayexpress

Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

Project description:Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

| PRJEB73586 | ENA

Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

Project description:Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

| PRJEB73596 | ENA

Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

Project description:Essential gene screening identifies the Bromodomain-Containing Protein BRPF1 as a new therapeutic target for endocrine therapy-resistant breast cancer

| PRJEB73598 | ENA

Bromodomain-containing protein BRPF1 as a therapeutic target for metastatic ovarian cancer

Project description:Bromodomain-containing protein BRPF1 as a therapeutic target for metastatic ovarian cancer

| PRJEB71498 | ENA

Essential gene screening identifies the bromodomain-containing protein BRPF1 as a new actionable target for endocrine therapy-resistant breast cancers.

Project description:Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide 'drop-out' screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.

| S-EPMC11304578 | biostudies-literature

Bromodomain-containing protein BRPF1 as a therapeutic target for metastatic ovarian cancer

Project description:Total RNA was extracted using TRIzol from PEO4 and OVCAR-3 cells treated for 72 hours with 10uM GSK6853 or DMSO as a control. In case of BRPF1 silencing experiment, RNA extraction was performed from cells transfected with BRPF-targeting siRNA or nontarget (scramble) siRNA 96 hours post-transfection using TRIzol and Zymo RNA Clean & Concentrator-5 columns. Indexed libraries were prepared starting from 1000 ng of total RNA according to Illumina Stranded Total RNA prep Ligation with Ribo-Zero Plus kit. Final libraries were sequenced at a concentration of 0,6 pM/lane on the Illumina Novaseq 6000 using S4 flowcell and v1.5 reagents. The current study was focused on the investigation of molecular mechanisms underlying the antiproliferative effect of BRPF1 inhibition or silencing in ovarian cancer. To this end, transcriptome changes induced by GSK6853 treatment in chemotherapy-resistant PEO4 and OVCAR-3 cells and BRPF1 silencing in OVCAR-3 cells were analysed.

2024-01-08 | E-MTAB-13663 | biostudies-arrayexpress

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