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Targeting the N-terminus of the androgen receptor for prostate cancer therapy

ABSTRACT: Targeting the N-terminus of the androgen receptor for prostate cancer therapy

PROVIDER: PRJNA669849 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12840204_1.fastq.gz	Fastqsanger.gz
	SRR12840204_2.fastq.gz	Fastqsanger.gz
	SRR12840205_1.fastq.gz	Fastqsanger.gz
	SRR12840205_2.fastq.gz	Fastqsanger.gz
	SRR12840206_1.fastq.gz	Fastqsanger.gz

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Targeting the N-terminus of the androgen receptor for prostate cancer therapy

Project description:All current clinically approved androgen deprivation therapies for prostate cancer (PCa) target the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR), although the N-terminal domain (NTD) is the main regulator of AR activity. Targeting the AR NTD directly is a challenge because of its intrinsic disordered nature and the lack of secondary structure and clefts for drugs to bind. Here, we make use of the cochaperone BAG1L that functions through the NTD to develop alternative AR inhibitors. We show that BAG1L binds to a short alpha-helical region of the AR NTD and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by a small molecule 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17) downregulates AR target gene expression and blocks proliferation of AR-positive PCa cells. Targeting a cochaperone as a surrogate to the AR NTD is therefore key to developing novel AR antagonists.

2021-07-01 | GSE159606 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L

Project description:Targeting the androgen receptor N-terminus via the cochaperone Bag-1L

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Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [ChIP-Seq]

Project description:Targeting the activation function-1 (AF-1) at the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the BAG domain of the cochaperone Bag-1L. Mutations in this domain or loss of Bag-1L abrogates AR signaling and reduces PCa growth. Correspondingly, Bag-1L protein levels increase with progression of primary prostate tumors to castration-resistant PCa, correlating inversely with patient response to abiraterone therapy. Intriguingly, BAG domain residues important for its interaction with the AR AF-1 overlap a potentially druggable pocket of this protein. Bag-1L is therefore a putative therapeutic target for the inhibition of AR AF-1 activity.

2017-08-23 | GSE89938 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-Seq KO]

2017-08-23 | GSE89917 | GEO

Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [RNA-seq C-terminal mutant]

2017-08-23 | GSE102183 | GEO

Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

Project description:Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance occurs when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or when constitutively active splice variants lacking the androgen binding domain entirely (e.g. ARV7) is expressed. In this study, we are reporting the discovery of novel AR-NTD covalent inhibitor 1‐chloro‐3‐[(5‐([(2S)‐3‐chloro‐2‐hydroxypropyl]amino)naphthalen‐1‐yl)amino]propan‐2‐ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and its known coactivators and interactors, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule AR-NTD inhibitor for the treatment of CRPC.

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Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC

Project description:Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC

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TMEFF2 and CD95L derived shRNAs promote prostate cancer cell death by targeting the essential androgen receptor pathway

Project description:A novel mechanism, Death Induced by Survival gene Elimination (DISE), has recently been described as a potential cancer therapy. DISE kills cancer cells through an RNA interference (RNAi) mechanism. We show that expression of certain shRNAs developed to target TMEFF2 promotes prostate cancer (PCa) cell death similar to DISE, and independently of TMEFF2 targeting/expression. In PCa cells, these shRNAs downregulate the androgen receptor (AR) and AR coregulatory genes, an effect that correlates with the presence of short seed matches in their 3’UTRs and which results in global androgen signaling inhibition and cell death. We have termed this mechanism Androgen Network DISE (AN-DISE). shL3, an shRNA to CD95L known to promote DISE in non-PCa cells, promotes AN-DISE in PCa cells by targeting the AR-signaling pathway.

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Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

Project description:Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration resistant prostate cancer (mCRPC) during treatment. Patients and Methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation states of genes previously implicated in prostate cancer progression were observed, and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression (TTP). Importantly, we also report that markers associated with a highly aggressive form of the disease, Neuroendocrine-CRPC, were associated with a faster TTP. Conclusion: Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

2020-09-04 | GSE152631 | GEO

Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq]

Project description:Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC [RNA-seq]

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