Identification of novel AR and O-GlcNAc co-regulated genes in prostate cancer cells
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ABSTRACT:
PROVIDER: PRJNA545840 | ENA |
REPOSITORIES: ENA
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Project description:Androgen receptor (AR) plays a central role in the development of prostate cancer. Increased expression of O-GlcNAc transferase (OGT) and O-GlcNAcylation are also implicated in metastatic prostate cancer. Increased O-GlcNAcylation in prostate cancer cells is associated with poor prognosis in patients. In this study, we employed chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq) to identify AR and O-GlcNAc binding sites in an attempt to identify novel co-regulatory mechanisms, biomarkers/druggable targets.
2022-06-24 | GSE132073 | GEO
Project description:AR regulated transcriptome in prostate cancer cells
| PRJNA463491 | ENA
Project description:It has been well established that the transcription factor androgen receptor (AR) is obligatory for prostate cancer (PCa) development and progression, but the precise role of the AR in these processes is still unclear. To dissect the role of AR in shaping the transcriptome of prostate cancer cells, RNA-seq data were obtained from AR-positive LNCaP cells treated with various regimens to manipulate endogenous AR signaling. LNCaP cells were cultured in normal medium containing fetal bovine serum (FBS) to represent an androgen-dependent (AD) growth state. To mimic the clinical androgen-deprivation-therapy (ADT) settings, cells were grown for 4 days in conditions of either depletion of androgen (i.e., medium containing charcoal:dextran stripped fetal bovine serum (CDSS)) or the presence of AR antagonist Enzalutamide (MDV3100, 10 μM) to represent androgen-independent (AI) growth states. Aside from the pharmaceutical modulations, we also utilized siRNA to knockdown AR. To examine the direct effects of AR signaling on gene transcription and splicing, cells were primed with CDSS for 3 days followed by treatment of 10nM dihydrotestosterone (DHT) for 8-9 hrs. Deep sequencing of rRNA-depleted total RNAs was performed in biological duplicates on abovementioned LNCaP cultures.
2020-03-04 | GSE114052 | 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:Androgen receptor (AR) orchestrates an intricate transcriptional regulatory network that governs prostate cancer initiation, development and progression. To understand this network in detail, we generated genome-wide maps of AR occupancy by ChIP-seq in LNCaP cells. We found NKX3-1, an androgen-dependent homeobox protein well-characterized for its role in prostate development and differentiation, being recruited to AR binding sites (ARBS) in response to androgen signaling. We identified 6,359 NKX3-1 binding sites, most of which overlapped with AR. In addition to its novel collaborative transcriptional role at well-known prostate cancer model genes, our binding and knockdown studies further suggested that NKX3-1 potentially regulates AR in a feed-forward manner. Integrative analysis of Oncomine molecular concepts showed that these androgen-regulated AR and NKX3-1 associated genes are significantly overexpressed in prostate carcinoma as well as advanced and recurrent prostate tumors. From our transcriptomic profiling and Gene Ontology analysis, we observed that AR and NKX3-1 co-regulate genes involved in "protein trafficking" processes, which are mandatory events in the integration of oncogenic signaling pathways leading to prostate cancer development and progression. Interestingly, we found that AR and NKX3-1 co-regulate several members of the RAB GTPase family of secretory/trafficking proteins via the involvement of FoxA1 in a ternary complex and we believe that these AR/NKX3-1/FoxA1 co-regulated RAB genes could serve as expression signatures in prostate carcinogenesis. More specifically, through functional analyses, we showed that NKX3-1, together with AR and FoxA1, could promote prostate cancer cell survival through activation of RAB3B expression. Collectively, our study has provided important insights into the hierarchical transcriptional regulatory network established between AR and NKX3-1 and sought to elucidate the important genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer. Genome-wide binding analyses of AR, NKX3-1 and FoxA1 in LNCaP with or without DHT (5alpha-dihydrotestosterone) stimulation using ChIP-Seq.
2011-11-16 | E-GEOD-28264 | biostudies-arrayexpress
Project description:Androgen receptor (AR) orchestrates an intricate transcriptional regulatory network that governs prostate cancer initiation, development and progression. To understand this network in detail, we generated genome-wide maps of AR occupancy by ChIP-seq in LNCaP cells. We found NKX3-1, an androgen-dependent homeobox protein well-characterized for its role in prostate development and differentiation, being recruited to AR binding sites (ARBS) in response to androgen signaling. We identified 6,359 NKX3-1 binding sites, most of which overlapped with AR. In addition to its novel collaborative transcriptional role at well-known prostate cancer model genes, our binding and knockdown studies further suggested that NKX3-1 potentially regulates AR in a feed-forward manner. Integrative analysis of Oncomine molecular concepts showed that these androgen-regulated AR and NKX3-1 associated genes are significantly overexpressed in prostate carcinoma as well as advanced and recurrent prostate tumors. From our transcriptomic profiling and Gene Ontology analysis, we observed that AR and NKX3-1 co-regulate genes involved in ‘protein trafficking’ processes, which are mandatory events in the integration of oncogenic signaling pathways leading to prostate cancer development and progression. Interestingly, we found that AR and NKX3-1 co-regulate several members of the RAB GTPase family of secretory/trafficking proteins via the involvement of FoxA1 in a ternary complex and we believe that these AR/NKX3-1/FoxA1 co-regulated RAB genes could serve as expression signatures in prostate carcinogenesis. More specifically, through functional analyses, we showed that NKX3-1, together with AR and FoxA1, could promote prostate cancer cell survival through activation of RAB3B expression. Collectively, our study has provided important insights into the hierarchical transcriptional regulatory network established between AR and NKX3-1 and sought to elucidate the important genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer. Gene expression profiling of LNCaP in response to ETOH (vehicle) or DHT (5α-dihydrotestosterone) stimulation across different treatment time-points using microarray.
2011-11-16 | E-GEOD-28596 | biostudies-arrayexpress
Project description:An aberrant androgen receptor (AR) transcriptional network underpins prostate cancer development. Even though the AR cistrome had been extensively studied in prostate cancers, information pertaining to the spatial architecture of the AR transcriptional circuitry remains limited due to the absence of an AR-associated chromatin interactome map. To resolve this, we utilized chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing to profile AR-associated and ERG-associated long range chromatin interactions in an ERG fusion positive prostate cancer cell line. We identified ERG-associated long range chromatin interactions as an elemental component in the AR-associated chromatin interactome, acting in concert, to achieve coordinated regulation of AR target genes. In addition, we characterized the epigenetic signature of the AR/ERG anchor binding sites and implicated AR and ERG associated chromatin loopings for facilitating fusion gene formation in prostate cancers. Taken together, our results revealed the presence of an AR/ERG defined higher order chromatin structure exploited for driving prostate cancer progression.
2018-12-14 | GSE54946 | GEO
Project description:Androgen receptor (AR) orchestrates an intricate transcriptional regulatory network that governs prostate cancer initiation, development and progression. To understand this network in detail, we generated genome-wide maps of AR occupancy by ChIP-seq in LNCaP cells. We found NKX3-1, an androgen-dependent homeobox protein well-characterized for its role in prostate development and differentiation, being recruited to AR binding sites (ARBS) in response to androgen signaling. We identified 6,359 NKX3-1 binding sites, most of which overlapped with AR. In addition to its novel collaborative transcriptional role at well-known prostate cancer model genes, our binding and knockdown studies further suggested that NKX3-1 potentially regulates AR in a feed-forward manner. Integrative analysis of Oncomine molecular concepts showed that these androgen-regulated AR and NKX3-1 associated genes are significantly overexpressed in prostate carcinoma as well as advanced and recurrent prostate tumors. From our transcriptomic profiling and Gene Ontology analysis, we observed that AR and NKX3-1 co-regulate genes involved in "protein trafficking" processes, which are mandatory events in the integration of oncogenic signaling pathways leading to prostate cancer development and progression. Interestingly, we found that AR and NKX3-1 co-regulate several members of the RAB GTPase family of secretory/trafficking proteins via the involvement of FoxA1 in a ternary complex and we believe that these AR/NKX3-1/FoxA1 co-regulated RAB genes could serve as expression signatures in prostate carcinogenesis. More specifically, through functional analyses, we showed that NKX3-1, together with AR and FoxA1, could promote prostate cancer cell survival through activation of RAB3B expression. Collectively, our study has provided important insights into the hierarchical transcriptional regulatory network established between AR and NKX3-1 and sought to elucidate the important genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.
2011-11-16 | GSE28264 | GEO
Project description:The activation of the androgen receptor (AR) through binding of androgens is essential for prostate tumorigenesis. Although significant effort has been devoted to determining the intrinsic mechanism underlying AR action and designing therapies to directly target AR expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using both in vivo tissue recombination assays and mouse models. Single-cell RNA sequencing combined with other experimental analyses showed that AR loss in stromal Gli1-lineage niches resulted in robust increased expression of insulin-like growth factor binding protein 3 (IGFBP3) through attenuation of AR suppression on Sp1-regulated transcription. Aberrant increased IGFBP3 further inhibits IGF1 induced Wnt signaling activation in subsets of basal epithelial cells, impairing oncogenic cell growth and tumor development. IGFBP3 further showed to attenuate IGF1-induced oncogenic growth of prostatic organoids derived from mouse basal epithelia. Loss of human prostate tumor basal cell signatures was identified in basal cells with AR-deficient microenvironment. This study demonstrates the niche effect of stromal AR in Gli1-lineage cells in supporting prostate tumorigenesis, implicating co-targeting tumor epithelial and stromal AR signaling for treating advanced prostate cancer.
2022-10-07 | GSE174471 | GEO
Project description:Androgen receptor (AR) orchestrates an intricate transcriptional regulatory network that governs prostate cancer initiation, development and progression. To understand this network in detail, we generated genome-wide maps of AR occupancy by ChIP-seq in LNCaP cells. We found NKX3-1, an androgen-dependent homeobox protein well-characterized for its role in prostate development and differentiation, being recruited to AR binding sites (ARBS) in response to androgen signaling. We identified 6,359 NKX3-1 binding sites, most of which overlapped with AR. In addition to its novel collaborative transcriptional role at well-known prostate cancer model genes, our binding and knockdown studies further suggested that NKX3-1 potentially regulates AR in a feed-forward manner. Integrative analysis of Oncomine molecular concepts showed that these androgen-regulated AR and NKX3-1 associated genes are significantly overexpressed in prostate carcinoma as well as advanced and recurrent prostate tumors. From our transcriptomic profiling and Gene Ontology analysis, we observed that AR and NKX3-1 co-regulate genes involved in ‘protein trafficking’ processes, which are mandatory events in the integration of oncogenic signaling pathways leading to prostate cancer development and progression. Interestingly, we found that AR and NKX3-1 co-regulate several members of the RAB GTPase family of secretory/trafficking proteins via the involvement of FoxA1 in a ternary complex and we believe that these AR/NKX3-1/FoxA1 co-regulated RAB genes could serve as expression signatures in prostate carcinogenesis. More specifically, through functional analyses, we showed that NKX3-1, together with AR and FoxA1, could promote prostate cancer cell survival through activation of RAB3B expression. Collectively, our study has provided important insights into the hierarchical transcriptional regulatory network established between AR and NKX3-1 and sought to elucidate the important genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer.
2011-11-16 | GSE28596 | GEO