Effects of OCT4/NRF1 knockdown in castration-resistant prostate cancer cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146656 | GEO | 2021/05/01
REPOSITORIES: GEO
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Project description:Prostate cancer is the most common cancer in men and androgen receptor (AR) downstream signalings promote prostate cancer progression. Although androgen deprivation therapy is effective for treating prostate cancer, most tumors relapsed as castration-resistant prostate cancer (CRPC). We performed ChIP-seq analysis to investigate the role of important transcription factors and histone modifications using AR positive prostate cancer cells, LNCaP, CRPC model cells, 22Rv1 and DU145 cells.
2021-05-01 | GSE146886 | GEO
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:More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naïve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. 4 samples in each group: androgen-dependent growth (AD), castration-induced regression nadir (ND), and castration-resistant regrowth (CR) stages
2010-06-08 | E-GEOD-21887 | biostudies-arrayexpress
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Although initially hormone-deprovation therapy is effective to inhibit cancer progression, most of cancers relapse as castration-resistant prostate cancer (CRPC). PSF is one of RNA binding proteins associated with prostate cancer progression. In this study, we examined the effect of small molecule treatment interacting with PSF in CRPC cells. In order to investigate the effect of small molecule interacting with PSF cells, we analyzed gene expression profile in AR-positive prostate cancer cell line LNCaP and CRPC model cell derived from LNCaP cells.We treated LNCaP cells with vehicle or dihydrotestosterone (DHT) for 24 h. LTAD cells were treated with siControl or siPSF (10 nM) for 48 h. LTAD cells were treated with vehicle or small molecule interacting with PSF (No.10-3) for 48 h.
2021-05-01 | GSE155804 | GEO
Project description:Androgen receptor (AR) pathway inhibition remains the cornerstone for first- and second-line prostate cancer therapies. Although AR signaling inhibitors, such as enzalutamide and abiraterone extend survival in recurrent and castration-resistant prostate cancer (CRPC), durable and complete responses are rare. Resistance mechanisms employed by metastatic CRPC include amplification of AR and AR splice variants in AR-positive CRPC (ARPC) and conversion to AR-null phenotypes, such as double-negative prostate cancer (DNPC) and small cell or neuroendocrine prostate cancer (SCNPC). We have shown previously that DNPC can bypass AR-dependence through fibroblast growth factor (FGF) signaling. However, the role of the fibroblast growth factor receptor (FGFR) pathway in other molecular subtypes of CRPC has not been elucidated.
2023-09-19 | GSE228283 | GEO
Project description:The spliced variant forms of androgen receptor (AR-Vs) have been identified recently in castration-resistant prostate cancer (CRPC) cell lines and clinical samples. Here we identified the cistrome and transcriptome landscape of AR-Vs in CRPC cell lines and determine the clinical significance of AR variants regulated gene.The AR variants binding sites can be identified in 22Rv1 cell line in the absence of androgen. Knocking down full-length AR (AR-FL) doesn't affect AR-Vs binding sites in genome-wide. A set of genes were identified to be regulated uniquely by AR-Vs, but not by AR-FL in androgen-depleted condition. Integrated analysis showed that some genes may be modulated by AR-Vs directly. Unsupervised clustering analysis demonstrated that AR variants gene signature can separate not only the benign and malignant prostate tissue, but also the localized prostate cancer and metastatic CRPC specimens. Some genes modulated uniquely by AR variants were also identified to correlate with the Gleason Pattern of prostate cancer and PSA failure. We conclude that AR spliced variants bind to DNA independent of full-length AR, and can modulate a unique set of genes which is not regulated by full-length AR in the absence of androgen. AR variants gene signature correlate with CRPC and prostate cnacer disease progress. Androgen receptor (AR) binding sites in human prostate cancer 22Rv1 cell lines were studied using ChIP-seq. ChIP enriched and input DNA were sequenced using Illumina HiSeq 2000.
2014-09-10 | E-GEOD-58478 | biostudies-arrayexpress
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Although initially hormone-deprovation therapy is effective to inhibit cancer progression, most of cancers relapse as castration-resistant prostate cancer (CRPC). Therefore, we examined the effect of AR interacting partner OCT1 in CRPC cells. In order to investigate the OCT1 function in CRPC cells, we performed gene expression in AR-positive CRPC cell line, 22Rv1, after siOCT1 treatment. We also treated cells with vehicle or dihydrotestosterone (DHT) to analyzed the effects of OCT1 on AR function.
2019-03-01 | GSE123517 | GEO
Project description:Clinical resistance such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) restrict the second-generation antiandrogens benefit in patients with castration-resistant prostate cancer (CRPC). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. In this study, based on rational drug design, we discovered and identified a bifunctional small molecule Z15 as a potent AR antagonist and AR selective degrader. Z15 could directly bind to the AR ligand-binding domain (LBD) and inhibited DHT-induced AR nuclear translocation. Furthermore, Z15 promoted AR degradation through the proteasome pathway. As a result, our in vitro and in vivo studies showed Z15 efficiently suppressed AR and AR mutant transcription activity, downregulated mRNA and protein levels of AR target genes, as well as overcame AR LBD mutations, AR amplification, and ARVs-induced resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
2023-02-02 | PXD035721 | Pride
Project description:Androgen receptor (AR) splice variants (ARVs) are implicated in developing castration-resistant (CR) prostate cancer (CRPC). Little is known about the ARV-mediated transcription program in CRPC. We identified ARV-preferred binding sites (ARV-PBS) and unique transcriptome in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions with the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions with the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in CR patients. ARV-driven genes were up-regulated in abiraterone-resistant patient specimens and promote CRPC growth. We uncover distinct genomic and epigenomic characteristics of ARV-PBS and a unique ARV-dependent transcriptional program that not only drives CR progression but could also offer new targets for therapy. Increasing evidence suggests a pivotal role of ARVs in the acquisition of anti-AR therapy resistance in CRPC. It has been shown previously that ARVs possess unique structural and functional features such as completely lacking or only containing an impaired ligand-binding domain but constitutively active. Our findings advance the understanding of ARVs by demonstrating that ARV-PBS exhibit distinctive DNA-binding motif, GC content, and nucleosome and epigenetic characteristics. We further unravel that ARV-PBS exclusively overlap with AR bindings identified from castration-resistant patients and ARV activity is significantly increased in abiraterone-resistant patients. Given that there is no drug available to target ARVs at present, identification of ARV-mediated unique downstream pathways opens new avenues for the development of effective therapeutics for CRPC.
2018-03-07 | GSE80742 | GEO
Project description:Androgen receptor (AR) splice variants (ARVs) are implicated in developing castration-resistant (CR) prostate cancer (CRPC). Little is known about the ARV-mediated transcription program in CRPC. We identified ARV-preferred binding sites (ARV-PBS) and unique transcriptome in CRPC cells. ARVs preferentially bind to enhancers located in nucleosome-depleted regions with the full AR-response element (AREfull), while full-length AR (ARFL)-PBS are enhancers resided in closed chromatin regions with the composite FOXA1-nnnn-AREhalf motif. ARV-PBS exclusively overlapped with AR binding sites in CR patients. ARV-driven genes were up-regulated in abiraterone-resistant patient specimens and promote CRPC growth. We uncover distinct genomic and epigenomic characteristics of ARV-PBS and a unique ARV-dependent transcriptional program that not only drives CR progression but could also offer new targets for therapy. Increasing evidence suggests a pivotal role of ARVs in the acquisition of anti-AR therapy resistance in CRPC. It has been shown previously that ARVs possess unique structural and functional features such as completely lacking or only containing an impaired ligand-binding domain but constitutively active. Our findings advance the understanding of ARVs by demonstrating that ARV-PBS exhibit distinctive DNA-binding motif, GC content, and nucleosome and epigenetic characteristics. We further unravel that ARV-PBS exclusively overlap with AR bindings identified from castration-resistant patients and ARV activity is significantly increased in abiraterone-resistant patients. Given that there is no drug available to target ARVs at present, identification of ARV-mediated unique downstream pathways opens new avenues for the development of effective therapeutics for CRPC.
2018-03-07 | GSE80741 | GEO