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Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [ATAC-seq]

ABSTRACT: Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [ATAC-seq]

PROVIDER: PRJNA1051085 | ENA |

REPOSITORIES: ENA

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Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation

Project description:Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation

| PRJNA1051080 | ENA

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [scRNA-seq]

Project description:Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [scRNA-seq]

| PRJNA1051091 | ENA

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [RNA-seq]

Project description:Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [RNA-seq]

| PRJNA1051092 | ENA

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [ChIP-seq]

Project description:Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [ChIP-seq]

| PRJNA1051084 | ENA

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [scRNA-seq]

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

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [RNA-seq]

2024-12-19 | GSE249888 | GEO

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [ChIP-seq]

2024-12-19 | GSE249887 | GEO

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [ATAC-seq]

2024-12-19 | GSE249886 | GEO

Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-12-19 | GSE249890 | GEO

Rb and p53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance

Project description:Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting lineage plasticity facilitates therapeutic resistance. Mechanisms underlying prostate cancer lineage plasticity are unknown, and relevant experimental models are needed. We demonstrate Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation in the mouse. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates mouse tumors are comparable to human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors like Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations enabling prostate cancer progression, identify mouse models for studying prostate cancer lineage plasticity, and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.

2017-02-24 | GSE90891 | GEO

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