Spermine restrains prostate cancer progression via targeting PRMT1
Description
The natural polyamine metabolite spermine exists in all eukaryotic cells. Prostate is the most abundant tissue in spermine. With prostate cancer (PCa) progression, the content of spermine is negatively correlated with tumor malignancy. Here we report that spermine inhibits PCa growth in vitro and in vivo through targeting the arginine methyltransferase 1 (PRMT1). We find that spermine inhibits the expression of AR-FL and AR-V7 signature genes by RNA sequencing analysis. Spermine acts as an endogenous inhibitor of PRMT1, it binds to PRMT1 and inhibits its enzymatic activity, reduces H4R3me2a modification at AR promoter and suppresses the chromatin accessibility of AR target genes, thus leads to reduced AR signaling. Genetic knockdown and pharmacologic inhibition of PRMT1 also inhibit AR signaling, and the capacity of spermine to inhibit AR signaling was abrogated by PRMT1 knockdown. Spermine and PRMT1 inhibitor DCPT1061 reduce AR-V7 signaling, showing better anti-tumor efficacy than enzalutamide in 22RV1-xenograft animal model which is castration resistant. Collectively, our findings uncover the anticancer function of spermine in PCa, and illustrate the metabolism-epigenetics crosstalk in which spermine inhibits AR signaling through targeting PRMT1, and suggest PRMT1 as a promising clinical druggable target for PCa.