p63-GATA2 molecular switch mediates the tumor suppressor to oncogene transition of glucocorticoid receptor in the prostate

Glucocorticoids are widely used to alleviate inflammation and treatment-related side effects in prostate cancer (PCa), particularly to counteract abiraterone-induced cortisol suppression. However, the glucocorticoid receptor (GR) exhibits a dual role exerting tumor-suppressive effects by inhibiting early-stage PCa cell proliferation, while also promoting oncogenic progression by mediating antiandrogen resistance. The molecular mechanisms underlying this functional dichotomy have remained elusive and poorly characterized. Using genome-wide analyses and CRISPR-based genome editing, we identified the tumor protein p63 as a key mediator of GR’s tumor-suppressive chromatin activity and maintenance of basal epithelial cell identity. Loss of p63 reprograms GR activity toward an oncogenic state, marked by basal-to-luminal transition, enhanced cell migration, invasion, and altered morphology accompanied by increased epithelial-mesenchymal transition markers. This functional shift is driven by elevated expression of transcription factors GATA2 and FRA1, which remodel GR’s chromatin binding and transcriptional output to activate oncogenic signaling pathways. Together, our findings uncover a molecular switch that governs the dual role of GR in PCa, establishing transcription factor crosstalk as a critical regulator of GR-driven oncogenic reprogramming and cellular plasticity. These findings establish a framework for understanding glucocorticoid-induced tumor suppression and highlight GATA2 and FRA1 as potential targets to mitigate GR-mediated resistance in PCa.