Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine prostate tumors
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE18478 | GEO | 2010/07/13
SECONDARY ACCESSION(S): PRJNA120215
REPOSITORIES: GEO
Similar Datasets
Project description:Neuroendocrine (NE) carcinoma and NE differentiation (NED) of human prostate tumor are hallmarks of aggressive human prostate cancer. Here we reveal that HIF-1a cooperation with FoxA2, a transcription factor expressed in NE tissue, is required for determining NE phenotype. Reduced HIF-1a expression, as seen in the E3 ubiquitin ligase Siah2 mutant mice, converted NE tumors to atypical hyperplasia when crossed with the TRAMPTg mice. Significantly, HIF-1a cooperation with FoxA2 enables the trans-activation of select HRE-regulated genes such as Hes6, Plod2 and Jmjd1a, whose expression is notably higher in metastatic prostate adenocarcinomas. Our findings disclose the requirement for spatial and timely regulation of FoxA2 and HIF-1a for NE/NED in prostate tumors. 12 prostate tumor samples were analyzed during normoxia and hypoxia, with different FOX/HIF genotypes. The pivotal samples are represented as duplicates.
2010-07-13 | E-GEOD-18478 | biostudies-arrayexpress
Project description:Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25% treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process.
2022-10-28 | GSE216118 | GEO
Project description:Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25% treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process.
2022-10-28 | GSE215943 | GEO
Project description:Metastatic and locally advanced prostate cancer is treated by pharmacological targeting of androgen synthesis and androgen response via androgen signaling inhibitors (ASI), most of which target the androgen receptor (AR). However, ASI therapy invariably fails after 1-2 years. Emerging clinical evidence indicates that in response to ASI therapy, the AR-positive prostatic adenocarcinoma can transdifferentiate into AR-negative neuroendocrine prostate cancer (NEPC) in 17-25% treated patients, likely through a process called neuroendocrine differentiation (NED). Despite high clinical incidence, the epigenetic pathways underlying NED and ASI therapy-induced NED remain unclear. By utilizing a combinatorial single cell and bulk mRNA sequencing workflow, we demonstrate in a time-resolved manner that following AR inhibition with enzalutamide, prostate cancer cells exhibit immediate loss of canonical AR signaling activity and simultaneous morphological change from epithelial to NE-like (NEL) morphology, followed by activation of specific neuroendocrine (NE)-associated transcriptional programs. Additionally, we observed that activation of NE-associated pathways occurs prior to complete repression of epithelial or canonical AR pathways, a phenomenon also observed clinically via heterogenous AR status in clinical samples. Our model indicates that, mechanistically, ASI therapy induces NED with initial morphological change followed by deactivation of canonical AR target genes and subsequent de-repression of NE-associated target genes, while retaining AR expression and transcriptional shift towards non-canonical AR activity. Coupled with scRNA-seq and CUT&RUN analysis, our model system can provide a platform for screening of potential therapeutic agents that may prevent ASI-induced NED or reverse the NED process.
2022-10-28 | GSE215653 | GEO
Project description:Fatal neuroendocrine (NE) prostate cancer evolves from castration-resistant adenocarcinoma as a mechanism of resistance to androgen deprivation/anti androgen receptor therapies. Evidence suggests the microenvironment as a possible source of soluble factors mediating neuroendocrine differentiation (NED), but molecular mechanisms are unknown. Using a transgenic mouse model we show that upon castration tumor cells up-regulate GRP78, which triggers a cascade leading to down-regulation of the matricellular protein SPARC in the nearby stroma. SPARC loss allows stroma cells to release IL-6, a known inducer of NED. A drug targeting GRP78 blocks NED in castrated mice. These events find correlation in prostate cancer patients developing focal NED after androgen deprivation therapies. Our results candidate SPARC and GRP78 for diagnostic and therapeutic purpose, respectively.
2021-07-30 | GSE156033 | GEO
Project description:Although hypoxia inducible factor-1a (HIF-1a) was originally identified as a transcriptional factor to adapt hypoxia, HIF-1a has also been shown to regulate metabolic pathways specific for cancer, including aerobic glycolysis, namely “Warburg effect”. However, the mechanisms by which HIF-1a mediates the metabolic pathway under normoxia are not fully understood. Here, we identified gamma-glutamylcyclotransferase (GGCT) as a novel regulator of HIF-1a. GGCT is a highly expressed protein in various cancer tissues. Knockdown of GGCT exerts anticancer effects both in vitro and in vivo; thus, it is considered a promising therapeutic target. In this study, we show that depleting GGCT downregulates the protein and mRNA expressions of HIF-1a in PC3 prostate cancer cells, and that overexpressing GGCT upregulates them in mouse fibroblast NIH3T3 cells. We also show that depleting GGCT downregulates HIF-1a downstream target genes involved in glycolysis, whereas overexpressing GGCT exhibits upregulation pattern in these genes. Furthermore, we suggest that GGCT induces the metabolic switch from citric acid cycle to glycolysis under normoxia. Additionally, we show that GGCT regulates expression of HIF-1a protein via AMPK-mTORC1-4EBP1 pathway in PC3 cells. These results indicate the GGCT plays a regulatory role in the expression of HIF-1a followed by glycolytic switch in cancer cells.
2020-07-17 | GSE154592 | GEO
Project description:Although hypoxia inducible factor-1a (HIF-1a) was originally identified as a transcriptional factor to adapt hypoxia, HIF-1a has also been shown to regulate metabolic pathways specific for cancer, including aerobic glycolysis, namely “Warburg effect”. However, the mechanisms by which HIF-1a mediates the metabolic pathway under normoxia are not fully understood. Here, we identified gamma-glutamylcyclotransferase (GGCT) as a novel regulator of HIF-1a. GGCT is a highly expressed protein in various cancer tissues. Knockdown of GGCT exerts anticancer effects both in vitro and in vivo; thus, it is considered a promising therapeutic target. In this study, we show that depleting GGCT downregulates the protein and mRNA expressions of HIF-1a in PC3 prostate cancer cells, and that overexpressing GGCT upregulates them in mouse fibroblast NIH3T3 cells. We also show that depleting GGCT downregulates HIF-1a downstream target genes involved in glycolysis, whereas overexpressing GGCT exhibits upregulation pattern in these genes. Furthermore, we suggest that GGCT induces the metabolic switch from citric acid cycle to glycolysis under normoxia. Additionally, we show that GGCT regulates expression of HIF-1a protein via AMPK-mTORC1-4EBP1 pathway in PC3 cells. These results indicate the GGCT plays a regulatory role in the expression of HIF-1a followed by glycolytic switch in cancer cells.
2020-07-17 | GSE154584 | GEO
Project description:Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance in early prostate cancer, other factors such as c-Myc and the E2F family also play a role in later stage disease. Hes6 is a transcription co-factor that has been associated with neurogenesis during gastrulation, a neuroendocrine phenotype in the prostate and metastasis in breast cancer but its role in prostate cancer remains uncertain. Here we show that Hes6 is controlled by c-Myc and AR and drives castration resistance in prostate cancer. Hes6 activates a cell-cycle enhancing transcriptional network that maintains tumour growth and nuclear AR localization in castrate conditions. We show aphysical interaction between E2F1 and both Hes6 and AR, and suggest a co-dependency of these transcription factors in castration-resistance. In the clinical setting, we have uncovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted. We have therefore shown for the first time the critical role of Hes6 in the development of CRPC and identified its potential in patient specific therapeutic strategies. This SuperSeries is composed of the SubSeries listed below.
2014-04-17 | GSE36526 | GEO
Project description:Neuroendocrine prostate cancer (NEPC) is a subset of castration-resistant prostate cancer (CRPC) and is thought to derive from prostate adenocarcinoma. However, the cellular basis responsible for Neuroendocrine differentiation (NED) is still under debate. Here, we characterized the tumor cell diversity of 6 CRPC patients using single cell RNA sequencing (scRNA-seq) and detected NED in four patients.
2020-09-01 | GSE137829 | GEO
Project description:Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance in early prostate cancer, other factors such as c-Myc and the E2F family also play a role in later stage disease. Hes6 is a transcription co-factor that has been associated with neurogenesis during gastrulation, a neuroendocrine phenotype in the prostate and metastasis in breast cancer but its role in prostate cancer remains uncertain. Here we show that Hes6 is controlled by c-Myc and AR and drives castration resistance in prostate cancer. Hes6 activates a cell-cycle enhancing transcriptional network that maintains tumour growth and nuclear AR localization in castrate conditions. We show aphysical interaction between E2F1 and both Hes6 and AR, and suggest a co-dependency of these transcription factors in castration-resistance. In the clinical setting, we have uncovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted. We have therefore shown for the first time the critical role of Hes6 in the development of CRPC and identified its potential in patient specific therapeutic strategies. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-04-17 | E-GEOD-36526 | biostudies-arrayexpress