A TBX2-driven signaling switch from Androgen Receptor to Glucocorticoid Receptor confers therapeutic resistance in Prostate Cancer

Recent studies suggest that glucocorticoid receptor (GR) activation can cause enzalutamide resistance in advanced prostate cancer (PCa) via functional bypass of androgen receptor (AR) signaling. However, the specific molecular mechanism(s) driving this process remain unknown. We previously reported that the transcription factor TBX2 is over-expressed in castrate resistant prostate cancer (CRPC). Our current study demonstrates that TBX2, which has known repressor and activator functions, is a molecular switch that represses AR levels while inducing GR expression to bypass AR-signaling. Mechanistically, our studies revealed that TBX2 binds to the promoters of both AR and GATA2, an AR coregulator, thereby resulting in a two-tiered repression of AR expression. Concurrently, TBX2 upregulated the GR via direct GR promoter binding and TBX2-GR protein-protein interaction. Together, TBX2-driven repression of the AR and activation of GR resulted in enzalutamide resistance. Significantly, we report that SP2509, an allosteric inhibitor of the demethylase-independent function of LSD1, a TBX2-interacting protein in the COREST complex, disrupted both TBX2-LSD1 and TBX2-GR protein-protein interactions thereby uncovering a unique mode of SP2509 action in CRPC. Taken together, our study provides key insights into a potential therapeutic modality for targeting the AR- to GR- signaling switch via disruption of TBX2-GR and TBX2-LSD1 protein-protein interactions.