Antiandrogen treatment endows ZMYDN8 dependent epigenetic reprogramming to orchestrate neuroendocrine tumor transdifferentiation [RNA-seq]
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. Overall design: To understand the cell lines changes in ZMYND8-OE condition, we treated cell lines with or without ZMYND8-OE and cultured with CSS (Charcoal-Stripped FBS) in three time points (day0, day3 and day30), which mimic the ADT progress. SiFOXM1 and inhibitor iZMYND8-34 treatment were used to rescue ZMYND8 function, while the control groups were EV and DMSO. The RNA-seq results of all the groups mentioned above to uncover the function of ZMYDN8 in ADT progress and the way to rescue its function or cure the disease caused by ZMYND8 overexpressed.