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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE249890 | GEO | 2024/12/19

REPOSITORIES: GEO

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

2024-12-19 | GSE249889 | GEO

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 [ATAC-seq]

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

| PRJNA1051085 | 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 [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 [RNA-seq]

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

| PRJNA1051092 | ENA

Stress, novel sex genes, and epigenetic reprogramming orchestrate socially controlled sex change.

Project description:Bluehead wrasses undergo dramatic, socially cued female-to-male sex change. We apply transcriptomic and methylome approaches in this wild coral reef fish to identify the primary trigger and subsequent molecular cascade of gonadal metamorphosis. Our data suggest that the environmental stimulus is exerted via the stress axis and that repression of the aromatase gene (encoding the enzyme converting androgens to estrogens) triggers a cascaded collapse of feminizing gene expression and identifies notable sex-specific gene neofunctionalization. Furthermore, sex change involves distinct epigenetic reprogramming and an intermediate state with altered epigenetic machinery expression akin to the early developmental cells of mammals. These findings reveal at a molecular level how a normally committed developmental process remains plastic and is reversed to completely alter organ structures.

| S-EPMC6620101 | biostudies-literature

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