Nandana, S. | Search bioRxiv

bioRxiv2024

TIAM1 signaling drives prostatic budding and branching phenotypes and is a potential therapeutic target for BPH

Benign prostatic hyperplasia (BPH) is the most prevalent urologic disease in men aged over 50 years. However, the molecular mechanisms that drive BPH pathophysiology remain elusive. In this study, we integrated bioinformatic and experimental analyses of human BPH to identify TIAM1-RAC1 signaling pathway as a promising candidate for a molecular-based approach for BPH therapy. First, elevated TIAM1 expression in a BPH transcriptomic signature that was generated from the analysis of RNA-seq data from three independent BPH patient cohorts was validated at the protein level in a fourth patient cohort. Additional bioinformatic analyses of the BPH transcriptomic signature pointed to TIAM1-RAC1 pathway as the potential lead therapeutic pathway; and NSC23766 - a small molecule inhibitor of TIAM1 signaling - as a developmental lead compound for BPH therapy. Next, a proof-of-concept pharmacological approach of TIAM1-RAC1 inhibition in human prostatic cells using NSC23766 resulted in attenuated organoid budding and branching - a developmental program associated with prostatic nodule formation and BPH pathogenesis. Finally, shRNA-based genetic knock-down of TIAM1 in human prostatic cells led to a reduction in budding and branching phenotypes thereby phenocopying the effects of NSC23766. Together, our observations implicate elevated TIAM1 as a driver of budding and branching in BPH, and our studies pave the way for TIAM1-RAC1 based targeted approach for the treatment of the disease.

cell biology↗

bioRxiv2023

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

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.

cancer biology↗