Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

Automated summary

In castration-resistant prostate cancer (CRPC), the limited response to androgen receptor (AR) antagonists is mainly attributed to the expression of AR-variants and restored AR signaling. We demonstrate that the metabolite spermine inhibits AR-FL and AR-V7 signaling and suppresses CRPC cell proliferation by directly binding and inhibiting PRMT1. Additionally, spermine supplementation restrains CRPC growth in vivo. Thus, spermine and PRMT1 inhibition may be powerful strategies for overcoming the limitations of current AR-based therapies in CRPC.