RNA-seq analysis regarding antiandrogen (enzalutamide) effect on gene expression in castration-resistant prostate cancer (CRPC) xenograft model
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147541 | GEO | 2022/05/02
REPOSITORIES: GEO
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Project description:Enzalutamide (ENZA) is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the response is only temporary and the disease almost always develops resistance. Given that many ENZA-resistant tumors are not driven by specific somatic mutations, there is increasing evidence that epigenetic factors can cause ENZA resistance. To explore how resistance arises we systematically tested all the epigenetic modifiers in castration-resistant and ENZA-resistant prostate cancer models using a custom epigenetic CRISPR library. From this, we identified and validated numerous epigenetic modifiers that were selectivity essential including SMARCC2, a core component of the SWI/SNF complex (or BAF complex) that regulates gene expression by altering DNA accessibility. Additionally, our data demonstrated canonical BAF complex dependency in ENZA-resistance that was also observed following the loss of DPF2, a canonical BAF-specific component. We showed that the chromatin occupancy of SMARCC2 and BRG1 was expanded in acquired ENZA resistance to the regions that overlap with transcriptional activity and CRPC-associated transcription factors that are significantly accessible in CRPC patients. Overall, our study revealed a regulatory role for SMARCC2 in ENZA-resistant prostate cancer and demonstrated the feasibility of targeting the SWI/SNF complex in late-stage PCa.
2024-12-13 | GSE280839 | GEO
Project description:Enzalutamide (ENZA) is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the response is only temporary and the disease almost always develops resistance. Given that many ENZA-resistant tumors are not driven by specific somatic mutations, there is increasing evidence that epigenetic factors can cause ENZA resistance. To explore how resistance arises we systematically tested all the epigenetic modifiers in castration-resistant and ENZA-resistant prostate cancer models using a custom epigenetic CRISPR library. From this, we identified and validated numerous epigenetic modifiers that were selectivity essential including SMARCC2, a core component of the SWI/SNF complex (or BAF complex) that regulates gene expression by altering DNA accessibility. Additionally, our data demonstrated canonical BAF complex dependency in ENZA-resistance that was also observed following the loss of DPF2, a canonical BAF-specific component. We showed that the chromatin occupancy of SMARCC2 and BRG1 was expanded in acquired ENZA resistance to the regions that overlap with transcriptional activity and CRPC-associated transcription factors that are significantly accessible in CRPC patients. Overall, our study revealed a regulatory role for SMARCC2 in ENZA-resistant prostate cancer and demonstrated the feasibility of targeting the SWI/SNF complex in late-stage PCa.
2024-12-13 | GSE284210 | GEO
Project description:RNA-seq analysis regarding antiandrogen (enzalutamide) effect on gene expression in castration-resistant prostate cancer (CRPC) xenograft model
| PRJNA615217 | ENA
Project description:Enzalutamide (ENZA) is a frequently used therapy in metastatic castration-resistant prostate cancer (mCRPC). Baseline or acquired resistance to ENZA have been observed, but the molecular mechanisms of resistance are poorly understood. We aimed to identify proteins involved in ENZA resistance and to find therapy-predictive serum markers. We performed comparative proteome analyses on ENZA-sensitive parental (LAPC4, DUCAP) and -resistant prostate cancer cell lines (LAPC4-ENZA, DUCAP-ENZA) using liquid chromatography tandem mass spectrometry (LC-MS/MS). The most promising 4 marker candidates were selected using bioinformatic approaches. Serum concentrations of selected markers (ALCAM, AGR2, NDRG1, IDH1) were measured in 72 ENZA-treated mCRPC patients’ samples using ELISA. In addition, ALCAM serum levels were measured in 101 Abiraterone (ABI) and 100 Docetaxel (DOC)-treated mCRPC patients. Results were correlated with clinical and follow-up data. The functional role of ALCAM in ENZA resistance was assessed in vitro using siRNA. Our proteome analyses revealed 731 significantly differentially abundant proteins between ENZA-sensitive and -resistant cells and our filtering methods identified 4 biomarker candidates. Serum analyses of these proteins revealed only ALCAM to be associated with poor patient survival. Furthermore, higher baseline ALCAM levels were associated with poor survival in ABI- but not in DOC-treated patients. In LAPC4-ENZA resistant cells, ALCAM silencing by siRNA knockdown resulted in significantly enhanced ENZA sensitivity. Our analyses revealed that ALCAM serum levels may help to identify ENZA- and ABI-resistant patients and may thereby help to optimize future clinical decision-making. Our functional analyses suggest the possible involvement of ALCAM in ENZA resistance.
2022-06-24 | PXD031847 | Pride
Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. We identified glucocorticoid receptor (GR) activity as modulator of enzalutamite sensitivity in the VCaP prostate cancer cell line. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. These expression profiling data demonstrate that GR transcriptional activity overlaps with that of AR in the VCAP model. VCAP cells growing in complete media were treated with the indicated drugs in biological triplicates for 24 hours prior to harvest.
2013-12-27 | E-GEOD-51872 | biostudies-arrayexpress
Project description:Molecular mechanisms underlying resistance to androgen deprivation therapy (ADT) and, in particular, to antiandrogen Enzalutamide, in treating castration-resistant prostate cancer (CRPC), remain incompletely understood. Through screening >120 CRPC patient samples, we observed 3 expression patterns of androgen receptor (AR) protein: primarily nuclear (nuc-AR), mixed nuclear/cytoplasmic expression (nuc/cyto-AR), and low/no expression (AR-/lo). Xenograft CRPC modeling in 4 models (i.e., LNCaP, VCaP, LAPC4, and LAPC9) recapitulated the 3 AR expression patterns in castration-resistant tumors developed from parental androgen-dependent tumors. Strikingly, although the 3 CRPC models that retained AR expression (LNCaP, VCaP, and LAPC4) responded, to different levels and in different kinetics, to Enzalutamide, the AR-/lo LAPC9 CRPC was completely refractory to Enzalutamide. By combining whole-genome RNA-Seq and biochemical analyses together with experimental combinatorial therapy in the LNCaP and LAPC9 models, we identified BCL-2 as a critical therapeutic target in both AR+/hi and AR-/lo, Enzalutamide-resistant CRPC models.
2018-08-01 | GSE88752 | GEO
Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. We identified glucocorticoid receptor (GR) activity as modulator of enzalutamite sensitivity in the VCaP prostate cancer cell line. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. These expression profiling data demonstrate that GR transcriptional activity overlaps with that of AR in the VCAP model.
2013-12-27 | GSE51872 | GEO
Project description:This study aimed to identify gene signatures induced by enzalutamide (ENZA) in hormone-sensitive (LNCaP) and hormone-resistant prostate cancer (PCa) cells. LNCaP and C4-2 cells were treated with ENZA alone or in combination with androgen deprivation therapy (ADT) and radiation (XRT). Through gene expression profiling, we identified that ENZA alone or in combination with ADT enhanced the effect the effect of XRT through immune-related pathways in LNCaP cells and metabolic pathways in C4-2 cells.Kaplan-Meier curve and Cox propotional hazard models showed that low expression of all the candidate genes except PTPRN2 were associated with tumor progression and recurrence in a PCa cohort.
2019-07-01 | GSE126881 | GEO
Project description:The transdifferentiation from adenocarcinoma following androgen deprivation therapy (ADT) is thought to be the primary process leading to the development of neuroendocrine prostate cancer (NEPC). However, it remains unclear how lineage factors interact with ADT to endow the lineage transition. Through an integrated analysis of NEPC-based CRISPR-Cas9 screening and scRNA-seq tracking of tumor transitions, we unveil that antiandrogen-induced ZMYND8-dependent epigenetic programming orchestrates the transdifferentiation of NEPC. We demonstrate that the ablation of Zmynd8 restricts NEPC development in Pten/Trp53/Rb1 knockout mouse models. Conversely, ASCL1-induced upregulation of ZMYND8 shapes the neuroendocrine (NE) lineage to confer resistance to AR-targeted therapy. Mechanistically, FOXM1, a key regulator in castration-resistant prostate cancer (CRPC), stabilizes ZMYND8 binding to chromatin regions harboring H3K4me1-K14ac modification and FOXM1 targeting. Antiandrogen treatment frees the SWI/SNF chromatin remodeling complex from AR, enabling its interaction with ZMYND8/FOXM1 to upregulate key NE lineage regulators (e.g., FOXA2, SOX2, and POU3F2), thus inducing transdifferentiation. Having identified ZMYND8's link to adverse disease outcomes in CRPC patients, we develop a small molecule, ZMYND8i-34, designed to selectively inhibit its histone recognition. In pre-clinical models, ZMYND8i-34 treatment effectively blocks NE transdifferentiation and curtails CRPC development. Together, our results highlight the importance of antiandrogen treatment endowing ZMYND8-dependent epigenetic reprogramming to orchestrate lineage fate and suggest that targeting ZMYND8 may hold the potential to restrict NEPC development and overcome treatment resistance.
2024-12-19 | GSE249889 | GEO
Project description:The transdifferentiation from adenocarcinoma following androgen deprivation therapy (ADT) is thought to be the primary process leading to the development of neuroendocrine prostate cancer (NEPC). However, it remains unclear how lineage factors interact with ADT to endow the lineage transition. Through an integrated analysis of NEPC-based CRISPR-Cas9 screening and scRNA-seq tracking of tumor transitions, we unveil that antiandrogen-induced ZMYND8-dependent epigenetic programming orchestrates the transdifferentiation of NEPC. We demonstrate that the ablation of Zmynd8 restricts NEPC development in Pten/Trp53/Rb1 knockout mouse models. Conversely, ASCL1-induced upregulation of ZMYND8 shapes the neuroendocrine (NE) lineage to confer resistance to AR-targeted therapy. Mechanistically, FOXM1, a key regulator in castration-resistant prostate cancer (CRPC), stabilizes ZMYND8 binding to chromatin regions harboring H3K4me1-K14ac modification and FOXM1 targeting. Antiandrogen treatment frees the SWI/SNF chromatin remodeling complex from AR, enabling its interaction with ZMYND8/FOXM1 to upregulate key NE lineage regulators (e.g., FOXA2, SOX2, and POU3F2), thus inducing transdifferentiation. Having identified ZMYND8's link to adverse disease outcomes in CRPC patients, we develop a small molecule, ZMYND8i-34, designed to selectively inhibit its histone recognition. In pre-clinical models, ZMYND8i-34 treatment effectively blocks NE transdifferentiation and curtails CRPC development. Together, our results highlight the importance of antiandrogen treatment endowing ZMYND8-dependent epigenetic reprogramming to orchestrate lineage fate and suggest that targeting ZMYND8 may hold the potential to restrict NEPC development and overcome treatment resistance.
2024-12-19 | GSE249888 | GEO