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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242282 | GEO | 2025/04/02

REPOSITORIES: GEO

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Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer. LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]). In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription. Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signalling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers - pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term. The enclosed files are from microarrays experiments after suppressing LSD1 with RNAi or stimulating cells with the androgen agonist dihydrotestosterone (DHT).

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

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