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Updated: Jul 23, 2025
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer
1School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
Abstract:
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.
Insights
Spermine, a prostate metabolite, inhibits castration-resistant prostate cancer (CRPC) growth by blocking protein arginine methyltransferase 1 (PRMT1) and androgen receptor (AR) signaling. This offers a new strategy to overcome limitations in current AR-based CRPC therapies.
Area of Science:
- Oncology
- Metabolomics
- Molecular Biology
Background:
- Castration-resistant prostate cancer (CRPC) exhibits limited response to androgen receptor (AR) antagonists, often due to AR variants.
- The role of spermine, a highly abundant prostate metabolite that decreases with cancer progression, is not well understood.
Purpose of the Study:
- To investigate the function of spermine in CRPC.
- To determine if spermine can overcome resistance to AR-targeted therapies.
Main Methods:
- Investigated spermine's effect on full-length AR (AR-FL) and AR splice variant 7 (AR-V7) signaling in CRPC cells.
- Assessed spermine's direct binding and inhibition of protein arginine methyltransferase 1 (PRMT1).
- Analyzed spermine's impact on epigenetic modifications (H4R3me2a, H3K27ac) at the AR locus and target genes.
- Evaluated spermine supplementation and PRMT1 inhibition in CRPC xenograft models.
Main Results:
- Spermine directly binds and inhibits PRMT1, suppressing both AR-FL and AR-V7 signaling.
- Spermine reduces key epigenetic modifications associated with AR activity and AR target gene expression.
- Spermine supplementation significantly restrains CRPC tumor growth in vivo.
- Pharmacological inhibition of PRMT1 also suppressed AR signaling and reduced CRPC growth.
Conclusions:
- Spermine acts as an anticancer metabolite by inhibiting PRMT1, leading to transcriptional suppression of AR signaling in CRPC.
- Spermine and PRMT1 inhibition represent promising therapeutic strategies to overcome resistance to current AR-based treatments for CRPC.
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