Abstract 4828: Dynamic androgen signaling orchestrates epithelial-mesenchymal transitions and epigenetic memory in prostate cancer

Abstract Prostate cancer is one of the most aging-associated malignancies, with incidence rising sharply in older men. Although hyperactivation of the androgen receptor (AR) promotes tumor growth and provides the rationale for androgen deprivation therapy (ADT), circulating androgen levels paradoxically decline with age. This contradiction underscores the need to interpret AR function in a context-dependent manner. Epithelial-mesenchymal transition (EMT) is a central driver of metastasis and a common stress-adaptation program. AR-targeted therapies, including ADT and enzalutamide, can induce partial EMT and promote aggressive tumor states, yet how prostate tumor cells dynamically modulate AR signaling during this process remains unclear. Here, we exposed androgen dependent prostate tumor cells to androgen withdrawal, enzalutamide, or TGFβ stimulation and profiled AR activity, EMT markers, and metastatic behaviors across distinct stages of stress adaptation. Both AR inhibition and TGFβ signaling triggered EMT, marked by early suppression of AR activity. This initial AR downregulation was required for tumor cells to acquire mesenchymal features and enhanced motility. After TGFβ is removed, steroidogenesis was recovered, gradually restoring AR signaling. Late-phase AR reactivation promoted mesenchymal-epithelial transition (MET), re-establishing epithelial identity and stabilizing cell state. Steroidogenesis was essential for this EMT-MET rebalancing, as its inhibition induce redox oxidative imbalance and disrupted the completion of the adaptive cycle. Cells completing this EMT-MET transition became more resistant to androgen deprivation, proliferated more rapidly in spheroid culture, and exhibited globally elevated histone propionylation, indicating the establishment of an epigenetic “memory” that reinforces tumor plasticity. Together, these findings define a dynamic AR-EMT-steroidogenesis circuit that governs prostate cancer plasticity and therapeutic adaptation. This model provides a potential explanation for the paradox of increased prostate cancer incidence despite declining androgen levels with age. It also suggests that restoring AR activity may suppress EMT and metastasis, and that targeting histone propionylation could prevent therapy-induced aggressiveness and synergize with AR-directed therapies. Citation Format: Zhongchi Li, John Blenis. Dynamic androgen signaling orchestrates epithelial-mesenchymal transitions and epigenetic memory in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4828.