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Gene Expression Analysis of metastatic CRPC cell line C4-2B treated with the dual BET-kinase inhibitor MA4-022-1

ABSTRACT: We identified BRD4 as an epigenetic regulator of the prostate lineage specific gene HOXB13 during progression of the disease from an androgen dependent to an androgen independent state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112298 | GEO | 2019/03/01

REPOSITORIES: GEO

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Identification of HOXB13 target genes responsive to BET inhibitors

Project description:We identified BRD4 as an epigenetic regulator of the prostate lineage specific gene HOXB13 during progression of the disease from an androgen dependent to an androgen independent state.

2019-03-01 | GSE112300 | GEO

Identification of HOXB13 binding sites in metastatic PC treated with Enzalutamide

Project description:HOXB13 is a developmentally regulated transcription factor, co-expressed along with the Androgen receptor (AR) in a majority of PCs. Previous studies have indicated context dependent roles of HOXB13 in the functional regulation of AR and enrichment of HOXB13 motifs in the AR cistrome. Our studies showed that genetic or pharmacological blockade of HOXB13 sensitized mCRPCs to Enzalutamide (ENZ, Xtandi), an anti-androgen that is currently deployed to treat mCRPC patients. To identify HOXB13-mediated mechanism of castration-resistance ChIP-sequencing was performed with the HOXB13-K13ac, or IgG antibodies in the metastatic prostate cancer cell line, C4-2B in vehicle treated as well as Enzalutamide treated cell lines. We demonstrated for the first time that BRD4, epigenetically regulates HOXB13 gene expression in PCs. Consistently, JQ1 the prototype BET inhibitor suppresses HOXB13 expression and inhibit mCRPC growth. ChIP-sequence analysis reveals that HOXB13 recruitment to the chromatin is not completely abrogated in Enzalutamide treated cells identify a subset of genes that may have potential role in CRPC proliferation, anti-androgen resistance and metastasis.

2022-01-30 | GSE125902 | GEO

Gene Expression Analysis of metastatic CRPC cell line C4-2B treated with the dual BET-kinase inhibitor MA4-022-1

Project description:Gene Expression Analysis of metastatic CRPC cell line C4-2B treated with the dual BET-kinase inhibitor MA4-022-1

| PRJNA445556 | ENA

Targeted Escalation of an Acetylated HOXB13-dependent Tyrosine Kinase Super-Enhancer Network Promotes Prostate Tumor Autonomy

Project description:While tissue and lineage-specific super-enhancers (SEs) regulate cell fate decision during development, the nature of Castration Resistant Prostate Cancer (CRPC)-specific SEs (CSEs) that drive resistance to AR-targeted therapies is unknown. Herein we report the lysine 13 (K13)-acetylation of Homeodomain transcription factor HOXB13 as a critical feature underlying CSE exclusivity. The histone acetyltransferase (HAT) CBP/p300 specifically acetylates HOXB13 (acK13-HOXB13) in prostate cancer cells. The acK13-HOXB13 enriched CSEs sprout at critical lineage genes such as the NKX3-1, Androgen receptor (AR), AR regulator ACK1/TNK2 a tyrosine-kinase and tyrosine kinase ligands associated with angiogenesis, including VEGFA and ANGPT2/ANGPTL3 to expedite prostate tumor autonomy.

2022-09-22 | GSE169133 | GEO

Targeted Escalation of Tyrosine Kinase Super-Enhancer Network Engineered by Acetylated HOXB13 Spurs Prostate Tumor Autonomy

Project description:While tissue and lineage-specific super-enhancers (SEs) regulate cell fate decision during development, the nature of Castration Resistant Prostate Cancer (CRPC)-specific SEs (CSEs) is unknown. Herein we report the lysine 13 (K13) acetylation of HOXB13 mediated by the histone acetyltransferase CBP/p300 regulates prostate tumor autonomy. The acK13-HOXB13 shadows H3K27ac at lineage specific SEs and surpasses it at CSEs. In contrast, mutation of HOXB13 at K13 sensitizes CRPCs to Enzalutamide, disables spheroid and xenograft tumor formation. Mechanistically, the acK13-HOXB13 interacts with chromatin remodeling bromodomain proteins to regulate tumor-specific CSE selection. These CSEs sprout at critical lineage genes NKX3-1, Androgen receptor (AR), AR regulator ACK1 tyrosine kinase and tyrosine kinase ligands regulating angiogenesis. Single-cell transcriptomic analysis of human prostate tumor organoids reveal ACK1 expression underlies sensitivity to the small molecule inhibitor (R)-9b over AR-targeted agents. Collectively, our studies reveal acK13-HOXB13 regulated epigenome as a key cog in prostate cancer cell autonomy.

2022-09-22 | GSE167506 | GEO

Comparison of the prostate cancer cell line LNCaP and its androgen insensitive derivative C4-2B

2007-08-07 | GSE7702 | GEO

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (ChIP-Seq)

Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling1-3. Despite the success of recently approved therapies targeting AR signaling such as abiraterone4-6 and second generation anti-androgens MDV3100 (enzalutamide)7,8, durable responses are limited, presumably due to acquired resistance. Recently JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies9-12. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ111,13. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of AR, BRD2, BRD3, BRD4, ERG, RNA Pol II and H3K27ac in prostate cancer cells with respect to BET inhibitors

2014-04-25 | E-GEOD-55062 | biostudies-arrayexpress

Comparison of the prostate cancer cell line LNCaP and its androgen insensitive derivative C4-2B

Project description:LNCaP and its androgen insensitive derivative were profiled in order to identify genes differentially expressed during the conversion to androgen insensitivity. This experiment was performed due to the presence of an ins(7;14) localizing the entire ETV1 locus to chr 14 in LNCaP and C4-2B prostate cancer cells. Keywords: cell type comparison LNCaP and C4-2B were both hybridized to Agilent Whole Human Genome Oligonucleotide Microarrays, with a commercially obtained pool of benign prostate RNA serving as the reference for both cell lines. Dye flips for both cell lines were also performed

2007-08-07 | E-GEOD-7702 | biostudies-arrayexpress

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer (microarray)

2014-04-25 | E-GEOD-55063 | biostudies-arrayexpress

Homo sapiens isolate:C4-2B

Project description:Epigenetic reprogramming with antisense oligonucleotides enhances the effectiveness of androgen receptor inhibition in castration-resistant prostate cancer

| PRJNA485991 | ENA

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