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

Abstract Recent studies have highlighted that androgen receptor (AR) signaling can be bypassed via activation of the glucocorticoid receptor (GR), and that this bypass drives enzalutamide resistance in advanced prostate cancer (PCa). However, the molecular mechanism(s) that drive the switch from AR to GR signaling remain unknown. We have previously reported that TBX2, a developmental T-box transcription factor (TF), is over-expressed in castrate resistant prostate cancer (CRPC) and that TBX2 drives the CRPC phenotype via cell-intrinsic and exosome-mediated paracrine modes. Our current study demonstrates that TBX2, a TF with known repressor and activator functions, may be the molecular switch that represses AR on one hand while activating GR expression on the other to drive CRPC. Mechanistically, our studies revealed a two-tiered mechanism of AR repression by TBX2 wherein TBX2 directly binds to the promoters of AR and GATA2, an AR coregulator, thereby resulting in the repression of AR as well as GATA2. Conversely, our results demonstrate that TBX2 mediates increased expression of GR via directly binding to the GR promoter, and through TBX2-GR functional protein-protein interaction. Our results demonstrate that the TBX2 driven switch from AR to GR signaling results in enzalutamide resistance since GR inhibition in the context of TBX2 over-expression attenuates enzalutamide resistance. Further, we present evidence that SP2509 based allosteric inhibition of Lysine Specific Demethylase 1 (LSD1), a protein that interacts with TBX2 as part of the Co-repressor of RE1-Silencing Transcription Factor (COREST) complex, is able to disrupt TBX2-GR interaction. Taken together, our study has identified TBX2 as the molecular switch that drives AR to GR signaling and thereby confers enzalutamide resistance in CRPC. Furthermore, our study provides key insights into a potential therapeutic strategy of targeting the AR to GR switch wherein SP2509-based allosteric inhibition of TBX2-LSD1 could be harnessed to target the TBX2-GR interaction, thereby resulting in the inhibition of enzalutamide resistance in CRPC.