A heterochromatin gene signature unveils HP1α mediating neuroendocrine prostate cancer development and aggressiveness
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE105033 | GEO | 2018/01/22
REPOSITORIES: GEO
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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
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 | GSE249887 | 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 | GSE249886 | GEO
Project description:Background: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that SRY-Box transcription factor 4 (SOX4) is upregulated in NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. Methods: To understand the function of SOX4 in the development and progression of NEPC, we detected malignancy characterization after over-expression or knock-down of SOX4 in prostate cancer cells. Xenograft tumors representing NEPC subtypes were analyzed by pathologists. Protein expression profiles were validated in patient tumor tissue. Diagnoses were complemented by transcriptome sequencing and ATAC sequencing of specific cell lines and public clinical datasets. Results: SOX4 expression was significantly elevated in NEPC. Activating SOX4 in non-NEPC cells induced NE transdifferentiation, while silencing it in NEPC cells impeded NEPC progression. SOX4 promote neuroendocrine characteristics by inducing PCK2-mediated metabolism changing. Conclusions: Elevated SOX4 drives NE transdifferentiation in PCa via PCK2-mediated . Altogether, these findings highlight SOX4 as a novel molecule to drive NEPC progression and suggest that it might be a potential therapeutic target for NEPC.
2024-03-31 | GSE261370 | GEO
Project description:Treatment-emergent neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of advanced prostate cancer that develops via NE transdifferentiation of prostate adenocarcinomas in response to androgen receptor (AR)-inhibition therapy. Study of t-NEPC has been hampered by a lack of clinically relevant models. We previously established a unique and first-in-field patient-derived xenograft (PDX) model of adenocarcinoma (LTL331)-to-NEPC (LTL331R) transdifferentiation. In this study, we applied conditional reprogramming (CR) culture to establish a LTL331 PDX-derived cancer cell line named LTL331_CR_Cell. LTL331_CR_Cells retain the same genomic mutations as the LTL331 parental tumor, can be continuously propagated in vitro, and can be genetically manipulated. Androgen deprivation treatment on LTL331_CR_Cells showed no effect on cell proliferation. Transcriptomic analyses comparing the LTL331_CR_Cell to its parental tumor revealed a profound downregulation of the androgen response pathway and an upregulation of stem and basal cell marker genes. The transcriptome of LTL331_CR_Cells partially resembles that of post-castrated LTL331 xenografts in mice. Notably, when grafted under the renal capsule of male NOD/SCID mice, LTL331_CR_Cells spontaneously give rise to NEPC tumors as manifested by the histological expression of the NE marker CD56 and the loss of adenocarcinoma markers such as PSA. Transcriptomic analyses of the newly developed NEPC tumors further demonstrate marked enrichment of NEPC signature genes and loss of AR signaling genes. This study provides a novel research tool based on a unique PDX model. It allows for the investigation of mechanisms underlying t-NEPC development by enabling gene manipulation ex vivo and subsequent functional evaluation in vivo.
2020-06-19 | GSE149091 | GEO
Project description:Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-indifferent neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the transition to NEPC suggests a model of lineage plasticity, where AR-dependent luminal tumors progress towards an AR-independent neuroendocrine (NE) lineage. Genetic analysis of human NEPC showed a frequent loss of RB1 and TP53, and in experimental models, loss of both genes facilitates the transition to a NE lineage. Transcriptomics has shown the lineage transcription factors ASCL1 and NEUROD1 are present in NEPC. In this study, we used genetically engineered mouse models harboring Cre induced loss of Rb1 and Trp53 with MycT58A overexpression (RPM), to model prostate adenocarcinoma with NEPC by establishing prostate organoids that are subsequently used to generate subcutaneous allograft tumors. These tumors are heterogeneous and display adenocarcinoma, squamous, and NE features. ASCL1 and NEUROD1 are expressed within the NE defined regions, with ASCL1 being more predominant than NEUROD1. Genetic loss of ASCL1 in this model does not decrease tumor growth or tumor formation, however, there is a notable decrease in NE identity and an increase in cells with basal-like cell identity. This study provides a new in vivo model to study the progression of prostate cancer to NEPC and establishes the requirement for ASCL1 in driving neuroendocrine differentiation.
2024-08-28 | GSE264598 | GEO
Project description:Introduction: Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer, exhibiting rapid progression and is unresponsive to hormone therapy. Reliable prognostic assays and more effective treatments are critically required. However, the research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we successfully developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation from prostate adenocarcinoma. By comparing gene expression profiles of the parental adenocarcinoma line (LTL331) and the NEPC subline (LTL331R), we identified DEK, a gene not previously reported in prostate cancer, as a potential biomarker and target for NEPC. Methods: DEK protein expression in patient tissue-derived xenograft models and clinical samples was assessed by immunohistochemistry. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis. Results: Elevated DEK protein expression was observed in all clinical NEPC cases, which is distinct from their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration resistant prostate cancer (29.55%). Increased DEK expression is an independent clinical risk factor and is associated with shorter disease free survival in hormonal naïve prostate cancer patients. Reduction of DEK expression in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. Conclusions: The results suggest that DEK may play an important role in the progression of prostate cancer, especially NEPC and provide a potential biomarker to aid risk stratification of prostate cancer and a novel therapeutic target for treating NEPC. The function of DEK was determined by siRNA-induced reduction of DEK expression in PC-3 cells, a cell line with NEPC characteristics, followed by functional assays and gene expression profiling analysis.
2015-01-15 | E-GEOD-61214 | biostudies-arrayexpress
Project description:MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC including the small cell prostate carcinoma (SCPC) variant with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate adenocarcinoma and NEPC can both arise from a common epithelial clone. Further, N-Myc is required for tumor maintenance and destabilization of N-Myc through Aurora A kinase inhibition reduces tumor burden. Our findings establish N-Myc as a driver of NEPC and a target for therapeutic intervention. Expression profiling by high throughput sequencing of experimentally generated human tumors with mixed NEPC and prostate adenocarcinoma. Gene expression analysis of laser capture microdissected NEPC and adenocarcinoma from three independent engineered human tumors of mixed NEPC and prostate adenocarcinoma phenotype.
2016-02-06 | E-GEOD-77624 | biostudies-arrayexpress
Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive form of prostate cancer characterized by the loss of androgen receptor (AR) signaling and the acquisition of neuroendocrine (NE) characteristics. However, the underlying molecular mechanism, especially related to the drivers or the determinants responsible for NE transdifferentiation, remains unclear. In this study, we compared gene expression profiling of NEPC and non-NEPC specimens and paid a particular attention to those transcriptional factors affecting neural differentiation during development. We identified that Paired box 6 (Pax6) expression was significantly elevated in NEPC and negatively regulated by AR signaling. While knock-down of Pax6 in NEPC cells inhibited NEPC phenotypes, over-expression of Pax6 in non-NEPC cells led to development of NEPC. Mechanistically, loss of AR resulted in an enhanced expression of Pax6, which reprogramed the lineage plasticity of prostate cancer cells to develop NE phenotypes through the c-Met/Stat5a signaling. By performing ATAC-seq, we found that high expression level of Pax6 elicited enhanced chromatin accessibility mainly through attenuation of H4K20me3 that usually causes chromatin silence in cancer cells. Taken together, these findings highlight PAX6 as a novel molecule to drive NEPC progression and suggest that it might serve as a potential target for the management of NEPC.
2024-01-09 | GSE250422 | GEO