Genome wide analysis of important transcription factors and histone modifications for prostate cancer progression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146886 | 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 of tumors relapsed as castration-resistant prostate cancer (CRPC). We performed ChIP-seq analysis to investigate the role of AR-associated factors and histone modifications using CRPC model cells, 22Rv1.
2019-04-01 | GSE123565 | GEO
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). In this study, we examined the effect of OCT4 or NRF1 knockdown in CRPC cells. In order to investigate the OCT4 and NRF1 function in CRPC cells, we performed gene expression in AR-positive CRPC cell line, 22Rv1, AR-negative CRPC cell lines, PC3-CR (Cabazitaxel resistant), DU145, and DU145-CR, after siOCT4 (10 nM) or siNRF1 (10 nM) treatment. We also treated cells with vehicle, ribavirin (riba), or dihydrotestosterone (DHT) to analyzed the effects of thiese drug treatments.
2021-05-01 | GSE146656 | 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: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: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). RNA binding protein PSF is upregulated in CRPC tissues comparedd with hormone-sensitive prostate cancer. Therefore, we examined the effect of newly developed small molecules targeting PSF in CRPC cells. In order to investigate the effect of PSF inhibiton in CRPC cells, we performed gene expression analysis in AR-negative CRPC cell line, DU145. We treated cells with vehicle, No.10-3, or C-30, which are supposed to inhibit PSF function.
2024-09-01 | GSE243001 | GEO
Project description:Prostate cancer is the most common cancer in men and androgen receptor (AR) downstream signalings promote prostate cancer cell proliferation. PSF is an RNA-binding protein which is involved in AR signaling. To investigate the role of PSF, we performed RNA immunoprecipitation (RIP) and crosslinking immunoprecipitation (CLIP) sequence analysis in AR-positive prostate cancer cell line, LNCaP. In addition, we used hormone-refractory prostate cancer model cells 22Rv1 and long term androgen deprivation (LTAD) cells to explore the differences of PSF function in prostate cancer progression.
2017-12-24 | GSE94243 | GEO
Project description:The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signalling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant prostate cancer (CRPC), AR activity remains critical for tumor growth despite androgen deprivation. While previous studies have focused on ligand-dependent AR signalling, in this study we explore AR function under the androgen-deprived conditions characteristic of CRPC. Our data demonstrate that the AR persistently occupies a distinct set of genomic loci after androgen deprivation in CRPC. These androgen-independent AR occupied regions have constitutively open chromatin structures that lack the canonical androgen response element and are independent of FoxA1, a transcription factor involved in ligand-dependent AR targeting. Many AR binding events occur at proximal promoters, which can act as enhancers to augment transcriptional activities of other promoters through DNA looping. We further show that androgen-independent AR binding directs a distinct gene expression program in CRPC, which is necessary for the growth of CRPC after androgen withdrawal. LNCaP, C4-2B, or 22RV1 cells were cultured in hormone-free media for 3 days and then treated with ethanol vehicle or DHT (10nM) for 4h or 16h prior to ChIP-seq or RNA-seq assays. For siRNA transfection, cells were transfected with AR siRNA or control siRNA for 3 days prior to RNA-seq assays.
2012-10-02 | E-GEOD-40050 | 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
Project description:The development and progression of castrate resistant prostate cancer (CRPC), a lethal disease, is thought to be driven by multiple events. A hallmark of CRPC is the ability to evade the cytotoxic effects of anti-androgen therapy. Importantly, persistent androgen receptor (AR) signalling is thought to play a principal role in maintaining CRPC. The precise molecular alterations driving this condition, however, are not clearly understood. Our previous studies identified specific metabolic alterations associated with localized prostate cancer (PCa) and CRPC, implicating metabolic re-programming in disease progression. Building on these findings, using a novel network-based integromics approach, here we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. We found expression of the HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) was regulated by androgens and elevated in androgen dependent (AD) PCa while relatively diminished in CRPC possessing either full length AR (AR-FL) or the spliced V7 variant (AR-V7). Genetic loss of function experiments for GNPNAT1 in CRPC-like cells led to increased proliferation and aggressiveness, both, in vitro and in vivo. This was mediated by specific cell cycle genes regulated by the PI3K-AKT pathway activating either AR in cells with AR-FL or SP1-ChREBP (carbohydrate response element binding protein) in cells containing AR-V7. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP) to CRPC-like cells reduced the expression of cell cycle genes and attenuated tumor cell proliferation, both in vitro and in vivo. Furthermore, addition of UDP sensitized CRPC-like cells, inclusive of those possessing AR-V7, to enzalutamide, demonstrating the therapeutic value of targeting altered metabolic pathways in lethal PCa. We anticipate that our findings will motivate the development of novel metabolic therapeutic strategies that complement existing treatments for men with lethal prostate cancer We used microarray analysis to determine key molecular alterations associated with inhibition of HBP pathway in CRPC by knocking down GNPNAT1 transcript level using lentiviral particle bearing shRNA in 22Rv1 and LNCaP-ABL cells GNPNAT1 expression was knockdown in two independent prostate cancer cells, 22Rv1 and LNCaP-ABL
2015-04-03 | E-GEOD-67537 | biostudies-arrayexpress