Direct ERG-to-glucocorticoid receptor interactions enhance tumorigenicity and might explain the enigmatic responses of prostate cancers to corticosteroids (ChIP-Seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE247347 | GEO | 2025/11/01
REPOSITORIES: GEO
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Project description:Patients with prostate cancer (PCa) frequently express fusions between an androgen-regulated gene and anETSfamily gene, especiallyERG. Our protein complementation assays revealed that the glucocorticoid receptor, GR, physically interacts with ERG. This alleviates allosteric autoinhibition, stabilizes ERG and protects it from chemotherapy-induced degradation. Promoter-reporter assays indicated that GR transactivates ERG’s target genes, includingMYC. In PCa models, antagonizing GR or lowering cortisol increased apoptosis and decreased tumorigenic growth of ERG-positive, not ERG-negative PCa cells. Likewise, ERG+patient-derivedxenografts displayedintensifiedsensitivity tothe combination of aGRantagonist and an inhibitor of the androgen receptor (AR). In summary, we uncovered an oncogenic partner of ERG, identified a potential molecular basis for the association of corticosteroid use with poor responses to AR signaling inhibitors, as well as offer new strategies to treat a sizable group of patients with PCa.
2025-11-01 | GSE247422 | GEO
Project description:We compared 22 primary Pca (hormone-dependent) versus 29 metastatic Pca (CRPC). The expression of genes related to cell cycle, proliferation, DNA synthesis, and androgen metablism are significantly increased in CRPC group. The expression of AR-stimulated genes were partially reactivated. TMPRSS2-ERG fusion status was determined for the samples by PCR. The expression of ERG was highly increased in fusion positive versus negative.
2011-09-22 | GSE32269 | GEO
Project description:The TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under the androgen receptor (AR) regulated expression of TMPRSS2. The T:E fusion is frequently associated with PTEN loss, and is highly correlated with decreased expression of INPP4B, both of which may compensate for ERG-mediated suppression of PI3K/AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses AKT activation, and that one potential mechanism is through downregulation of IRS2. In contrast, ERG knockdown did not increase INPP4B, suggesting its decreased expression is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression is similarly decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a function distinct from regulation of PI3K activity. As ERG expression in T:E fusion tumors is AR regulated, we further assessed the extent to which AR inhibition increased AKT activity in T:E fusion tumors. T:E fusion positive versus negative PDXs had greater increases in AKT activity after castration. Moreover, in a neoadjuvant trial of AR inhibition prior to radical prostatectomy we similarly found greater increases in AKT activation in the T:E fusion tumors. Together these findings indicate that AKT activation may mitigate the efficacy of AR targeted therapy in T:E fusion PCa, and that these patients may most benefit from combination therapy targeting AR and AKT.
2025-09-10 | GSE289100 | GEO
Project description:The TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under the androgen receptor (AR) regulated expression of TMPRSS2. The T:E fusion is frequently associated with PTEN loss, and is highly correlated with decreased expression of INPP4B, both of which may compensate for ERG-mediated suppression of PI3K/AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses AKT activation, and that one potential mechanism is through downregulation of IRS2. In contrast, ERG knockdown did not increase INPP4B, suggesting its decreased expression is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression is similarly decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a function distinct from regulation of PI3K activity. As ERG expression in T:E fusion tumors is AR regulated, we further assessed the extent to which AR inhibition increased AKT activity in T:E fusion tumors. T:E fusion positive versus negative PDXs had greater increases in AKT activity after castration. Moreover, in a neoadjuvant trial of AR inhibition prior to radical prostatectomy we similarly found greater increases in AKT activation in the T:E fusion tumors. Together these findings indicate that AKT activation may mitigate the efficacy of AR targeted therapy in T:E fusion PCa, and that these patients may most benefit from combination therapy targeting AR and AKT.
2025-09-10 | GSE289099 | GEO
Project description:We profiled androgen receptor (AR) genomic targets using high-throughput sequencing of chromatin-immunoprecipitated (ChIP) DNA from TMPRSS2-ERG fusion gene positive DUCaP prostate cancer cells. ChIp-seq and microarray gene expression profiling datasets were integrated with the NHGRI GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Eighty GWAS index or linked SNPs were found to be localized in ARBSs. Among these rs11891426:T>G in the 7th intron of the melanophilin gene was found located within a novel putative auxiliary AR binding motif, which we found enriched in the neighborhood of canonical androgen responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay of prostate cancer cell models. It went also in line with decreased melanophilin protein level in primary prostate tumors with G allele.These results unravel a hidden link between androgen receptor and a functional PCa risk SNP, whose allele alteration affects androgen regulation of its host gene melanophilin . Genomic profile of androgen receptor binding sites of androgen or vehicle treated DUCaP cells using ChIP-seq. IgG precipiated DNAs from both treatments served as controls.
2015-07-10 | E-GEOD-70679 | biostudies-arrayexpress
Project description:The androgen receptor (AR) serves as the primary target for therapeutic intervention in prostate cancer (PCa), and AR-targeted treatments constitute the cornerstone of clinical management for this malignancy. Nevertheless, their effectiveness is often compromised by the emergence of resistance mechanisms. These resistant forms of PCa persist in activating AR signaling, highlighting the urgent need for new therapeutic strategies to combat therapy-resistant PCa. Resistance to AR-targeted therapies can manifest through a multitude of mechanisms, including the overexpression of AR splice variants and altered activities of other transcription factors, such as the glucocorticoid receptor (GR) and FOXA1. A shared characteristic among these transcription factors is their dependence on a common set of coregulators, with EP300/CREBBP being a prominent example. This suggests a compelling rationale for employing coregulatory-targeted therapies in the management of treatment-resistant PCa. Here, we aimed to explore the impact of EP300/CREBBP acetyltransferase inhibition on steroid receptor and FOXA1 signaling in PCa cells, employing genome-wide techniques. Our findings illuminate that EP300/CREBBP inhibition exerts a substantial disruptive effect on the AR-regulated transcriptome and receptor chromatin binding, primarily by downregulating the AR-gene. Similarly, the transcriptome regulated by GR and the chromatin binding of the receptor were also hindered, although this was not associated with decreased GR expression levels. Instead, EP300/CREBBP acetyltransferase inhibition leads to a significant reduction in FOXA1 chromatin binding, consequently constraining GR signaling. In summary, our results emphasize how EP300/CREBBP acetyltransferase inhibition distinctly curtails the signaling activities of oncogenic transcription factors, underscoring the potential effectiveness of coregulatory-targeted therapies in PCa.
2024-03-14 | GSE245968 | GEO
Project description:The androgen receptor (AR) serves as the primary target for therapeutic intervention in prostate cancer (PCa), and AR-targeted treatments constitute the cornerstone of clinical management for this malignancy. Nevertheless, their effectiveness is often compromised by the emergence of resistance mechanisms. These resistant forms of PCa persist in activating AR signaling, highlighting the urgent need for new therapeutic strategies to combat therapy-resistant PCa. Resistance to AR-targeted therapies can manifest through a multitude of mechanisms, including the overexpression of AR splice variants and altered activities of other transcription factors, such as the glucocorticoid receptor (GR) and FOXA1. A shared characteristic among these transcription factors is their dependence on a common set of coregulators, with EP300/CREBBP being a prominent example. This suggests a compelling rationale for employing coregulatory-targeted therapies in the management of treatment-resistant PCa. Here, we aimed to explore the impact of EP300/CREBBP acetyltransferase inhibition on steroid receptor and FOXA1 signaling in PCa cells, employing genome-wide techniques. Our findings illuminate that EP300/CREBBP inhibition exerts a substantial disruptive effect on the AR-regulated transcriptome and receptor chromatin binding, primarily by downregulating the AR-gene. Similarly, the transcriptome regulated by GR and the chromatin binding of the receptor were also hindered, although this was not associated with decreased GR expression levels. Instead, EP300/CREBBP acetyltransferase inhibition leads to a significant reduction in FOXA1 chromatin binding, consequently constraining GR signaling. In summary, our results emphasize how EP300/CREBBP acetyltransferase inhibition distinctly curtails the signaling activities of oncogenic transcription factors, underscoring the potential effectiveness of coregulatory-targeted therapies in PCa.
2024-03-14 | GSE245967 | GEO
Project description:The androgen receptor (AR) serves as the primary target for therapeutic intervention in prostate cancer (PCa), and AR-targeted treatments constitute the cornerstone of clinical management for this malignancy. Nevertheless, their effectiveness is often compromised by the emergence of resistance mechanisms. These resistant forms of PCa persist in activating AR signaling, highlighting the urgent need for new therapeutic strategies to combat therapy-resistant PCa. Resistance to AR-targeted therapies can manifest through a multitude of mechanisms, including the overexpression of AR splice variants and altered activities of other transcription factors, such as the glucocorticoid receptor (GR) and FOXA1. A shared characteristic among these transcription factors is their dependence on a common set of coregulators, with EP300/CREBBP being a prominent example. This suggests a compelling rationale for employing coregulatory-targeted therapies in the management of treatment-resistant PCa. Here, we aimed to explore the impact of EP300/CREBBP acetyltransferase inhibition on steroid receptor and FOXA1 signaling in PCa cells, employing genome-wide techniques. Our findings illuminate that EP300/CREBBP inhibition exerts a substantial disruptive effect on the AR-regulated transcriptome and receptor chromatin binding, primarily by downregulating the AR-gene. Similarly, the transcriptome regulated by GR and the chromatin binding of the receptor were also hindered, although this was not associated with decreased GR expression levels. Instead, EP300/CREBBP acetyltransferase inhibition leads to a significant reduction in FOXA1 chromatin binding, consequently constraining GR signaling. In summary, our results emphasize how EP300/CREBBP acetyltransferase inhibition distinctly curtails the signaling activities of oncogenic transcription factors, underscoring the potential effectiveness of coregulatory-targeted therapies in PCa.
2024-03-14 | GSE245966 | GEO
Project description:We compared 22 primary Pca (hormone-dependent) versus 29 metastatic Pca (CRPC). The expression of genes related to cell cycle, proliferation, DNA synthesis, and androgen metablism are significantly increased in CRPC group. The expression of AR-stimulated genes were partially reactivated. TMPRSS2-ERG fusion status was determined for the samples by PCR. The expression of ERG was highly increased in fusion positive versus negative. 120 snap-frozen CT-guided bone marrow biopsies from patients with castration-resistant prostate cancer were collected as a source of material. 29 independent biopsies containing mostly tumor were identified as CRPC group through carefully microscopical examination. 4 samples containing no tumor were identified as normal bone marrow group. Primary tumor was isolated by LCM from frozen biopsies of hormone-naive patients. 22 samples were selected as primary PCa group.
2011-09-21 | E-GEOD-32269 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is a transcription factor that plays a central role in the growth and development of the normal prostate and its malignant transformation. More recently, a majority of prostate cancers have been shown to harbor recurrent gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor ERG. Here we employed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-Seq) to explore the genome-wide localization of these transcription factors in human prostate cancer cell lines as well as tissues. Unexpectedly, transcriptional networks emanating from AR and ERG were found to be highly overlapping. Furthermore, AR was found to regulate known 5’ fusion partners in prostate cancer including TMPRSS2, as well as negatively regulating its own expression. While induced by androgen through fusion to TMPRSS2, ERG itself was shown to inhibit AR expression and positively regulate the genomic locus of wild-type ERG, thus revealing multiple levels of molecular cross-talk between AR and ERG. Importantly, androgen-sensitive prostate cancer cells in which ERG is overexpressed are able to proliferate and invade in the absence of androgen. Thus, we dissected the intertwined genomic landscape of two master transcriptional regulators of prostate cancer and suggest a role for ERG in maintaining transcriptional networks necessary for androgen-independent prostate cancer growth. These studies may suggest that future therapies against prostate cancer should target both AR and ERG, rather than AR alone, in order to achieve maximum effectiveness. ChIP_Seq examination of histone modifications and key transcription factors in LNCaP and VCaP prostate cancer cell lines in un-treated, vehicle treated or 10nM R1881 treated conditions. LNCaP ChIP-Seq experiments include samples GSM353609-GSM353618, GSM353625-GSM353628, GSM353633-GSM353635, GSM353641-GSM353644, and GSM353648. VCaP ChIP-Seq experiments include samples GSM353601-GSM353608, GSM353619-GSM353624, GSM353629-GSM353632, and GSM353645-GSM353647. In addition, we performed re-ChIP of AR and ERG in VCaP cells (GSM356767), and examined the effect of ERG knockdown on AR and ERG binding (samples GSM353636-GSM353639). To study ectopic ERG binding we performed ERG ChIP-Seq in stable RWPE+ERG or control cells (samples GSM353649-GSM353650). AR ChIP-Seq was also done in the AR-positive but ETS fusion-negative 22RV1 cells (GSM353640). To further study transcription factor binding and chromatin state we performed ChIP-Seq of AR, ERG, H3K4me3, H3K9me3, H3K27me3 and RNA Pol II in a metastatic prostate tumor tissue (samples GSM353651-GSM353656). To couple the ChIP-Seq experiments with gene expression, we have also done Illumian SAGE-tag profiling in LNCaP cells following androgen treatment for 0, 24 and 48hrs. These DGE experiments correspond to samples GSM353657-GSM353659.
2010-05-17 | E-GEOD-14092 | biostudies-arrayexpress