Genome-wide AR chromatin association in human lung adenocarcinoma cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184311 | GEO | 2024/09/01
REPOSITORIES: GEO
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Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.
2023-10-11 | MTBLS8034 | MetaboLights
Project description:Overexpression of androgen receptor (AR) is the primary cause of castration-resistant prostate cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNAseq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ~50% of AR and SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR for AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. The SMAD3 peak in AR intron 3 overlapped with H3K27ac ChIP-seq and ATAC-seq peaks in datasets of prostate cancer. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. A SMAD3 PROTAC inhibitor reduced levels of AR, AR-V7 and AR targets in prostate cancer cells. This study suggests that SMAD3 could be targeted to inhibit AR in prostate cancer.
2023-01-12 | GSE211945 | GEO
Project description:Overexpression of androgen receptor (AR) is the primary cause of castration-resistant prostate cancer, although mechanisms upregulating AR transcription in this context are not well understood. Our RNAseq studies revealed that SMAD3 knockdown decreased levels of AR and AR target genes, whereas SMAD4 or SMAD2 knockdown had little or no effect. ChIP-seq analysis showed that SMAD3 knockdown decreased global binding of AR to chromatin. Mechanistically, we show that SMAD3 binds to intron 3 of the AR gene to promote AR expression. Targeting these binding sites by CRISPRi reduced transcript levels of AR and AR targets. In addition, ~50% of AR and SMAD3 ChIP-seq peaks overlapped, and SMAD3 may also cooperate with or co-activate AR for AR target expression. Functionally, AR re-expression in SMAD3-knockdown cells partially rescued AR target expression and cell growth defects. The SMAD3 peak in AR intron 3 overlapped with H3K27ac ChIP-seq and ATAC-seq peaks in datasets of prostate cancer. AR and SMAD3 mRNAs were upregulated in datasets of metastatic prostate cancer and CRPC compared with primary prostate cancer. A SMAD3 PROTAC inhibitor reduced levels of AR, AR-V7 and AR targets in prostate cancer cells. This study suggests that SMAD3 could be targeted to inhibit AR in prostate cancer.
2023-01-12 | GSE211944 | GEO
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Oct1 is an AR interacting partner and regulates the transcriptional activity of AR. In order to investigate the Oct1 function in prostate cancer cells, we performed gene expression in AR-positive prostate cancer cell lines after siOct1 or pyrrole-imidazole (PI) polyamide targeting Oct1-binding treatment. We also treated cells with vehicle or androgen to analyze the effects of Oct1 on AR function. Observation of androgen dependent gene expression changes after treatment with siOct1 or polyamide targeting Oct1 with microarray.
2016-04-01 | E-GEOD-77650 | biostudies-arrayexpress
Project description:Activation and transcriptional reprograming of AR in advanced prostate cancer frequently overlaps with the loss of two tumor suppressors, INPP4B and PTEN, which are highly expressed in human and mouse prostate epithelium. While regulation of AR signaling by PTEN has been described by multiple groups, it is not known whether the loss of INPP4B affects AR activity. Using prostate cancer cell lines we showed that INPP4B regulates AR transcriptional activity and oncogenic signaling pathways Akt and PKC. Analysis of gene expression in prostate cancer patient cohorts showed a positive correlation between INPP4B expression and both AR mRNA levels and AR transcriptional output. Using an Inpp4b-/- mouse model, we demonstrated that INPP4B suppresses Akt and PKC signaling pathways and modulates AR transcriptional activity in normal mouse prostate. It has been previously shown that the high fat diet activates Akt pathway in mouse prostate. We showed that the loss of INPP4B further increases Akt phosphorylation in dorsolateral and ventral lobes of mice fed with the high fat diet. Remarkably, PTEN protein levels and phosphorylation of S380 were the same in Inpp4b-/- and WT males, suggesting that observed changes were due exclusively to the loss of INPP4B. Our data show that INPP4B modulates AR activity in normal prostate and its loss contributes to the AR-dependent transcriptional profile in prostate cancer.
2021-03-12 | GSE111725 | GEO
Project description:The androgen receptor (AR) is an androgen-activated nuclear receptor. The androgen signaling axis is critical in all stages of prostate cancer, although the mechanism by which it contributes to tumorigenesis remains unclear. Mutations in the AR have been detected in prostate tumors; one such mutant, E231G, exhibits increased ligand sensitivity in the presence of specific cofactors. Mice with prostate-specific expression of AR-E231G invariably develop prostatic intraepithelial neoplasia (PIN) by 12 weeks, and metastatic prostate cancer by 52 weeks. To determine a potential mechanism of AR-driven tumorigenesis in AR-E231G mice, we compared gene expression profiles in prostates of 12 week old AR-E231G mice with another AR-variant mouse strain (AR-T857A) that does not develop tumors. Pathway classification of the 132 candidate genes differentially expressed in AR-E231G mouse prostates compared to AR-T857A mouse prostates revealed enrichment for groups important in prostate cancer, including “cancer,” “fatty acid metabolism” and “cell cycle” pathways. Two genes significantly upregulated in the AR-E231G model were Adm and Cited1. siRNA suppression of ADM and CITED1 expression by up to 63% and 79%, respectively, in LNCaP human prostate cancer cells, resulted in an approximate 1.8-fold increase in cell death. Cell proliferation was reduced by 35% when CITED1 mRNA expression was suppressed, but not significantly altered by ADM suppression. A gene signature set derived from this model was able to distinguish between primary Gleason grade 3 and Gleason grade 4 tumors (p=0.04237), and between human non-malignant and cancerous prostate in a test (p=0.02352) and validation cohort (p=7.53x10-9), highlighting the relevance of the AR-E231G model to the human disease. RNA was extracted from ventral prostate tissue from 12-week old AR-E231G and AR-T857A mice in FVB background. Pooled RNA from 3 mice per genotype were extracted using the RNeasy kit (Qiagen, Germantown, MD, USA), and 10 µg RNA was hybridized to a total of 2 Affymetrix Mouse Genome 430 2.0 chip® microarrays. Microarray data was normalized by Robust Multiarray Averaging. Probes with expression changes were identified using a fold-change cut-off of log1.5. Normalized microarray data was analysed using Ingenuity Pathways Analysis (IPA, Redwood City, CA, USA).
2013-10-01 | E-GEOD-24567 | biostudies-arrayexpress
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. We identified RUNX1 is an androgen-regulated gene. In order to investigate the RUNX1 function in prostate cancer cells, we performed gene expression in AR-positive prostate cancer cell lines after siRUNX1 treatment. We also treated cells with vehicle or androgen to analyzed the effects of RUNX1 on AR function. Observation of androgen dependent gene expression changes after treatmet with siRNAs targeting RUNX1 with microarray.
2014-10-18 | E-GEOD-62454 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is reactivated in castration resistant prostate cancer (CRPC) through mechanisms including marked increases in AR gene expression. We identify an enhancer in the AR second intron contributing to increased AR expression at low androgen levels in CRPC. Moreover, at increased androgen levels the AR binds this site and represses AR gene expression through recruitment of lysine specific demethylase 1 (LSD1) and H3K4me1,2 demethylation. AR similarly represses expression of multiple genes mediating androgen synthesis, DNA synthesis and proliferation, while stimulating genes mediating lipid and protein biosynthesis. Androgen levels in CRPC appear adequate to stimulate AR activity on enhancer elements, but not on suppressor elements, resulting in increased expression of AR and AR repressed genes that contribute to cellular proliferation. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile pre-castrated androgen dependent, 4d-post-castrated, and relapsed castration resistant VCaP xenograft tumors in 3 mice. Total RNA was isolated and amplified prior to hybridization against a common reference pool of prostate tumor cell lines.
2011-08-15 | E-GEOD-31410 | biostudies-arrayexpress
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Project description:We performed androgen receptor (AR) ChIP-seq after GFP control or FOXA1 over-expression in two AR driven cancer models; LNCaP prostate cancer cell line and MDA-MB-453 molecular apocrine breast cancer cell line.
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