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Effects of small molecules targeting the androgen receptor DNA-binding domain on prostate cancer cell transcriptome

ABSTRACT: Effects of small molecules targeting the androgen receptor DNA-binding domain on prostate cancer cell transcriptome

PROVIDER: PRJNA525448 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8667410.fastq.gz	Fastqsanger.gz
	SRR8667401.fastq.gz	Fastqsanger.gz
	SRR8667411.fastq.gz	Fastqsanger.gz
	SRR8667402.fastq.gz	Fastqsanger.gz
	SRR8667412.fastq.gz	Fastqsanger.gz

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Effects of small molecules targeting the androgen receptor DNA-binding domain on prostate cancer cell transcriptome

Project description:Prostate cancer is a leading cause of cancer related death among men. Current Androgen Receptor (AR) antagonists often target the ligand binding domain (LBD). However, occurrence of resistance to drugs targeting the LBD is common due to emergence of mutations in the LBD or constitutively active variants that lack the LBD itself. Two novel small molecules, VPC-17005 and VPC-14449 targeting the DNA-binding domain have been developed and published previously. In this study, LNCaP cells were treated with one of these drugs or the well-established AR antagonist Enzalutamide, and the transcriptomic changes have been determined using RNA-seq analysis.

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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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Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules

Project description:The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex becomes frequently deregulated in advanced castration-resistant prostate cancer (CRPC). SWI/SNF ATPase degrader molecules, also known as Proteolysis targeting chimera (PROTAC), offer a novel approach to tackle resistance to androgen receptor (AR) antagonists in AR-dependent CRPC (CRPC-AR). However, the frequent emergence of AR-negative CRPC remains a major clinical hurdle. We investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment reduced the viability of both CRPC-AR and WNT-signaling dependent CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT, we characterized that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the AP-1/MAPK signaling axis in this subtype of CRPC.

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Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules

Project description:The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex becomes frequently deregulated in advanced castration-resistant prostate cancer (CRPC). Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT). We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the WNT master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT.

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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.

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gene differentially expressed in androgen independent prostate cancer

Project description:Progression to androgen independent is the main cause of death in prostate cancer, and the mechanism is still unclear. By reviewing the expression profiles of 26 prostate cancer samples in a holistic view, we found a group of genes differentially expressed in androgen independent compared with androgen dependent groups (p value< 0.01, t test). Focusing on apoptosis, proliferation, hormone and angiogenesis, we found a group of genes such as thioredoxin domain containing 5 (TXNDC5), tumor necrosis factor receptor superfamily, member 10a (TNFRSF10A), ribosomal protein S19 (RPS19) and Janus kinase 2 (JAK2) up-regulated in androgen independent prostate cancer, which could play important roles in the transition from androgen dependent to androgen independent and could be biomarkers of prognosis. The main aim was comparing the androgen dependent and androgen independent prostate cancer to identify differentially expressed genes. In addition, we added several normal prostate tissue sample for comparisons. Totally 29 experiments were performed without replicates. 3 for normal prostate tissue, 8 for androgen independent cancer and 18 for androgen dependent prostate cancer. In all experiments, the reference samples are common reference, a pool with unrelated fetal tissues.

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