Lysine-specific demethylase 1 metastasis of androgen-independent PCa cells [ChIP-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE57077 | GEO | 2017/04/25
SECONDARY ACCESSION(S): PRJNA245396
REPOSITORIES: GEO
Similar Datasets
Project description:The aim of this study is to identify the LSD1 target genes in metastatic androgen independent prostate cancer Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer.
2017-04-25 | GSE57078 | GEO
Project description:Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen and the estrogen receptor, in synergy with androgen, are essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen plays in prostate carcinogenesis, and the precise mechanisms involved, remain unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor Beta (ERβ) agonist (genistein) and the inhibitory action of an anti-estrogen (ICI 182, 780) in patient-derived PCa xenograft models mimicking localized and metastatic disease. In this study, we compared the gene expression profiles of treated and untreated PCa xenografts using microarrays to identify a unique set of genes that were both up-regulated by genistein treatment and down-regulated by the anti-estrogen, ICI 182,780. Five of the six genes identified from this comparison belonged to the metallothionein (MT) gene family. Knock-down of ERβ led to a reduction in MT gene expression, confirming its role in regulating these genes. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumour lines, both of which were originally derived from the same PCa patient. Together our data provides evidence for the role of ERβ signalling in PCa metastasis and implicates estrogen-stimulated MT gene expression in this process. Three samples each (total RNA extracted from three tumours of three different animals from each group) for control, genistein and ICI were used for the array.
2012-12-27 | E-GEOD-43146 | biostudies-arrayexpress
Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer. LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]). In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription. Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signalling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers - pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term. The enclosed files are from microarrays experiments after suppressing LSD1 with RNAi or stimulating cells with the androgen agonist dihydrotestosterone (DHT).
2016-06-30 | E-GEOD-61630 | biostudies-arrayexpress
Project description:Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen and the estrogen receptor, in synergy with androgen, are essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen plays in prostate carcinogenesis, and the precise mechanisms involved, remain unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor Beta (ERβ) agonist (genistein) and the inhibitory action of an anti-estrogen (ICI 182, 780) in patient-derived PCa xenograft models mimicking localized and metastatic disease. In this study, we compared the gene expression profiles of treated and untreated PCa xenografts using microarrays to identify a unique set of genes that were both up-regulated by genistein treatment and down-regulated by the anti-estrogen, ICI 182,780. Five of the six genes identified from this comparison belonged to the metallothionein (MT) gene family. Knock-down of ERβ led to a reduction in MT gene expression, confirming its role in regulating these genes. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumour lines, both of which were originally derived from the same PCa patient. Together our data provides evidence for the role of ERβ signalling in PCa metastasis and implicates estrogen-stimulated MT gene expression in this process.
2012-12-27 | GSE43146 | GEO
Project description:Metastatic prostate cancer (PCa) is a terminal disease and establishment of novel therapeutic strategy specifically targeting metastasis is critically required for its management. This study was aimed at identifying metastasis-driving genes which could potentially be therapeutic targets for metastatic prostate cancer. Integrative analysis of gene expression profiles from a pair of metastatic and non-metastatic prostate cancer tissue xenografts was used to identify potential prostate cancer metastasis-driving genes. Among the candidate genes found, GATA2, a master regulator gene in the development of hematopoietic system, was particularly interesting since it is an important pioneer factor in the regulation of AR-target gene in prostate cancer. In consistent with our finding, elevated expression of the GATA2 gene in metastatic prostate cancers was found and its expression was significantly correlated with poor prognosis in prostate cancer patients. Furthermore, indication of the GATA2 gene maybe the metastasis-driving gene was evidenced in decreased of cell migration, tissue invasion and focal adhesion disassembly in GATA2-down-regulated LNCaP cells. Global gene expression analysis after silencing of the GATA2 gene revealed a significant changed in cell transcriptomes with ~ 2500 genes with > 2 fold mRNA level changed and FDR <0.05, indicates that GATA2 plays a critical role in cell reprogramming as pioneer factor in the development of prostate cancer metastasis. LNCaP human prostate cancer cells transiently knockdown with siRNA that specifically targeting GATA2 (siGATA2) or scrambled siRNA (sicontrol). RNAs were isolated from cells after 72 hours of incubation. Gene expression profiles of four biological replicates from each sample group were analyzed to identify differentially regulated downstream genes after knockdown of GATA2.
2014-01-20 | E-GEOD-49342 | biostudies-arrayexpress
Project description:The high mortality of prostate cancer (PCa) patients is primarily due to metastasis, which can be associated with castration-resistant PCa. Therefore, understanding the mechanisms controlling metastatic processes remains essential to improve the success of targeted therapies. The Rac1/Cdc42 regulator CdGAP (Cdc42 GTPase-activating protein) has been implicated in fundamental cellular processes involved during cancer progression. Here, we demonstrate that elevated CdGAP expression is associated with early biochemical relapse (BCR) and bone metastasis in PCa patients. Furthermore, gene expression analysis of CdGAP in PCa data sets revealed a positive association between high CdGAP expression and early BCR. CdGAP protein and mRNA levels were elevated in PC-3 cells with high metastatic potential compared to low levels of CdGAP in the androgen receptor positive LNCaP cell line. Knockdown of CdGAP in PC-3 cells reduced cell motility, invasion, proliferation and colony-formation ability while inducing an increase in cell apoptosis. Conversely, overexpression of CdGAP in DU-145 cells increased cell migration and invasion. Using global gene expression approaches we found that CdGAP regulates the expression of genes involved in EMT, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice showed a delayed tumor initiation and attenuated tumor growth. Orthotopic prostate injection of CdGAP-depleted PC-3 cells reduced cancer metastasis to kidneys, bones, and testis. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a novel biomarker and potential target for prostate cancer treatments.
2021-08-12 | GSE160399 | GEO
Project description:Epithelial-to-mesenchymal transition (EMT) and cancer stem cells play relevant roles in metastasis and drug resistance in castration-resistant prostate cancer (PCa). Conditioned-media from Cancer-Associated Fibroblasts from two patients with aggressive PCa induce EMT, reversible DNA methylation and transcriptional variations in androgen independent PC3, but not in androgen dependent LN-CaP cells. Focal CpG islands hyper-methylation associated to transcriptional repression of epithelial markers occurs together with widespread hypo-methylation, including promoters of EMT and stemness regulating genes resulting in their transcriptional activation. Remarkably, DNA methylation and transcription patterns are entirely reverted upon exposure to serum-free medium (mesenchymal-to-epithelial transition). DNMT3A is required for de novo methylation and silencing of CDH1 and GRHL2, the ZEB1 direct repressor, while its knock-down prevents EMT entry. These unprecedented results highlight that CAF-released factors induce reversible DNA methylation patterns required for transcriptional variations essential for EMT and stemness in androgen independent PCa cells, suggesting that similar plasticity might occur in tumour microenvironment. This submission contains data and metadata from the methylation profiling by array of PC-3 cells treated with conditioned media from Human prostate fibroblasts (HPFs) and cancer associated fibroblasts (CAFs).
2017-03-03 | E-MTAB-4753 | biostudies-arrayexpress
Project description:Purpose: Despite that androgen-deprivation therapy results in long-lasting responses, the disease inevitably progresses to metastatic castration-resistant prostate cancer. In this study, we identified miR-33b-3p as a suppressor of metastasis in prostate cancer. miR-33b-3p was significantly reduced in prostate cancer tissues, and the low expression of miR-33b-3p was correlated with poor overall survival of prostate cancer patients. Overexpression of miR-33b-3p inhibited both migration and invasion of highly metastatic prostate cancer cells whereas antagonizing miR-33b-3p promoted those processes in lowly metastatic cells. The in vivo results demonstrate that miR-33b-3p suppresses metastasis of tail vein inoculated prostate cancer cells to lung, liver, and lymph node in mice. DOCK4 was validated as the direct target of miR-33b-3p. miR-33b-3p decreased the expression of DOCK4 and restoration of DOCK4 could rescue miR-33b-3p inhibition on cell migration and invasion. Moreover, downregulation of miR-33b-3p was induced by bortezomib, the clinically used proteasome inhibitor, and overexpression of miR-33b-3p rescued the insufficient inhibition of bortezomib on migration and invasion in prostate cancer cells. Collectively, our findings demonstrate that miR-33b-3p suppresses metastasis by targeting DOCK4 in prostate cancer. Our results suggest that enhancing miR-33b-3p expression may provide a promising therapeutic strategy for overcoming that proteasome inhibitor’s poor efficacy against metastatic prostate cancer.
2021-09-08 | GSE183428 | GEO
Project description:Metastatic prostate cancer (PCa) is a terminal disease and establishment of novel therapeutic strategy specifically targeting metastasis is critically required for its management. This study was aimed at identifying metastasis-driving genes which could potentially be therapeutic targets for metastatic prostate cancer. Integrative analysis of gene expression profiles from a pair of metastatic and non-metastatic prostate cancer tissue xenografts was used to identify potential prostate cancer metastasis-driving genes. Among the candidate genes found, GATA2, a master regulator gene in the development of hematopoietic system, was particularly interesting since it is an important pioneer factor in the regulation of AR-target gene in prostate cancer. In consistent with our finding, elevated expression of the GATA2 gene in metastatic prostate cancers was found and its expression was significantly correlated with poor prognosis in prostate cancer patients. Furthermore, indication of the GATA2 gene maybe the metastasis-driving gene was evidenced in decreased of cell migration, tissue invasion and focal adhesion disassembly in GATA2-down-regulated LNCaP cells. Global gene expression analysis after silencing of the GATA2 gene revealed a significant changed in cell transcriptomes with ~ 2500 genes with > 2 fold mRNA level changed and FDR <0.05, indicates that GATA2 plays a critical role in cell reprogramming as pioneer factor in the development of prostate cancer metastasis.
2014-01-20 | GSE49342 | GEO
Project description:Background: Androgen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer (PCa). Despite the good initial response, castration resistance and metastatic progression will inevitably occur. Cancer-associated fibroblasts (CAFs) may be implicated in promoting metastasis of PCa after ADT. Our aim is to investigate the role and mechanism of CAF-derived exosomes involving in metastasis of PCa after ADT. Methods: PCa cells were co-cultured with exosomes derived from DHT-treated or ETOH-treated CAFs, and their migration and invasion differences under castration condition were examined both in vitro and in vivo. The miRNA profiles of exosomes derived from DHT-treated CAFs and matched ETOH-treated CAFs were analysed via next generation sequencing. The transfer of exosomal miR-146a-5p from CAFs to PCa cells was identified by fluorescent microscopy. The function and direct target gene of exosomal miR-146a-5p in PCa cells were confirmed through Transwell assays, luciferase reporter, and western blot. Findings: Compared with DHT-treated CAFs, exosomes derived from ETOH-treated CAFs dramatically increase migration and invasion of PCa cells under castration condition. MiR-146a-5p level in exosomes from ETOH-treated CAFs was significantly reduced. The loss of miR-146a-5p may strengthen the epithelial-mesenchymal transition (EMT) to accelerate cancer cells metastasis by modulating epidermal growth factor receptor (EGFR)/ERK pathway. Interpretation: CAFs-derived exosomal miR-146a-5p confers metastasis in PCa cells under ADT through the EGFR/ERK pathway and it may present a new treatment for PCa.
2022-08-02 | GSE154215 | GEO