Cell Reports (Jul 2023)

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

  • Xiao Li,
  • Fei Li,
  • Fei Ye,
  • Haotian Guo,
  • Wentao Chen,
  • Jia Jin,
  • Yiran Wang,
  • Pengfei Dai,
  • Huili Shi,
  • Hongru Tao,
  • Wenzhen Dang,
  • Yiluan Ding,
  • Mingchen Wang,
  • Hualiang Jiang,
  • Kaixian Chen,
  • Naixia Zhang,
  • Dong Gao,
  • Yuanyuan Zhang,
  • Cheng Luo

Journal volume & issue
Vol. 42, no. 7
p. 112798

Abstract

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Summary: 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.

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