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

doi:10.1016/j.celrep.2023.112798

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

Cell Rep. 2023 Jul 25;42(7):112798. doi: 10.1016/j.celrep.2023.112798. Epub 2023 Jul 14.

Authors

Xiao Li¹, Fei Li², Fei Ye³, Haotian Guo⁴, Wentao Chen⁵, Jia Jin⁶, Yiran Wang⁷, Pengfei Dai⁸, Huili Shi⁸, Hongru Tao⁹, Wenzhen Dang⁹, Yiluan Ding⁹, Mingchen Wang⁹, Hualiang Jiang⁹, Kaixian Chen⁹, Naixia Zhang⁹, Dong Gao¹⁰, Yuanyuan Zhang¹¹, Cheng Luo¹²

Affiliations

¹ School 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.
² State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
³ School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; College of Life Sciences and Medicine, Zhejiang SciTech University, Hangzhou 310018, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; China Pharmaceutical University, Nanjing 210009, P.R. China.
⁵ 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.
⁶ College of Life Sciences and Medicine, Zhejiang SciTech University, Hangzhou 310018, China.
⁷ School 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.
⁸ University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China; State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
⁹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
¹⁰ State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: dong.gao@sibcb.ac.cn.
¹¹ 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. Electronic address: yyzhang@simm.ac.cn.
¹² School 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; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China; China Pharmaceutical University, Nanjing 210009, P.R. China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China. Electronic address: cluo@simm.ac.cn.

PMID: 37453063
DOI: 10.1016/j.celrep.2023.112798

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.

Keywords: AR-FL; AR-V7; CP: Cancer; CRPC; Metabolite; PRMT1; Spermine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen Receptor Antagonists / therapeutic use
Cell Line, Tumor
Humans
Male
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Protein-Arginine N-Methyltransferases / genetics
Protein-Arginine N-Methyltransferases / metabolism
Receptors, Androgen* / metabolism
Repressor Proteins / metabolism
Signal Transduction
Spermine / pharmacology

Substances

Receptors, Androgen
Spermine
Androgen Receptor Antagonists
PRMT1 protein, human
Protein-Arginine N-Methyltransferases
Repressor Proteins