p63-GATA2 molecular switch mediates the tumor suppressor to oncogene transition of glucocorticoid receptor in the prostate
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Although glucocorticoids are widely used to alleviate side effects of prostate cancer (PCa) treatment, 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 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. Loss of p63 reprograms GR activity toward an oncogenic state, marked by enhanced cell migration, invasion, and altered morphology. This shift is driven by increased GATA2 expression, which alters GR’s chromatin binding and transcriptional output. Together, our findings uncover a p63–GATA2 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.
