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

• Published in: Cell reports (Cambridge) 2023-07, Vol.42 (7), p.112798-112798, Article 112798
• Main Authors: Li, Xiao, Li, Fei, Ye, Fei, Guo, Haotian, Chen, Wentao, Jin, Jia, Wang, Yiran, Dai, Pengfei, Shi, Huili, Tao, Hongru, Dang, Wenzhen, Ding, Yiluan, Wang, Mingchen, Jiang, Hualiang, Chen, Kaixian, Zhang, Naixia, Gao, Dong, Zhang, Yuanyuan, Luo, Cheng
• Format: Article
• Language: English
• Subjects: AR-FL; AR-V7; CP: Cancer; CRPC; Metabolite; PRMT1; Spermine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112798

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. [Display omitted] •Spermine suppresses CRPC progression by inhibiting both AR-FL and AR-V7 signaling•PRMT1 is a biological target of spermine in prostate cancer cells•Spermine reduces H4R3me2a at AR promoter and suppresses the transcription of AR-FL and AR-V7•Spermine and PRMT1 inhibition have significant antitumor effects in CRPC models Li et al. show that spermine, a natural metabolite, inhibits CRPC progression by suppressing AR-FL and AR-V7 signaling. Spermine targets PRMT1, reduces H4R3me2a modification at the AR locus, and suppresses both AR-FL and AR-V7 transcription. Spermine supplementation and PRMT1 inhibition have antitumor effects in CRPC models.