SAT1 promotes prostate cancer progression and decreases enzalutamide sensitivity by enhancing spermine catabolism

Prostate cancer is a major contributor to cancer-related mortality in men, and enzalutamide is a primary treatment option for advanced prostate cancer. Polyamines are ubiquitous amine molecules involved in tumorigenesis, cancer development, and drug resistance. This study aims to explore how spermidine/ spermine N1-acetyltransferase 1 (SAT1)-mediated polyamine metabolism influences prostate cancer progression and enzalutamide sensitivity. Through comprehensive bioinformatics screening, SAT1 was identified as a key regulator negatively associated with spermine abundance in prostate cancer. Analyses of clinical samples showed that increased SAT1 expression was positively linked to higher Gleason scores and more nodal metastases. Functional assays confirmed that knocking down SAT1 suppressed cancer cell proliferation, migration, invasion, and enzalutamide resistance, whereas overexpressing SAT1 enhanced these phenotypes. By promoting spermine catabolism, SAT1 triggered the activation of the JAK1/STAT3 pathway. Xenograft mouse models revealed that SAT1 knockdown inhibited tumor growth and improved the response to enzalutamide via the spermine-JAK1/STAT3 signaling axis. Notably, STAT3 gene was a transcriptional regulator of SAT1. These findings uncover a novel mechanism by which SAT1 facilitates tumor progression and decreases enzalutamide sensitivity, highlighting its potential as a therapeutic target for prostate cancer.