ZDHHC9 and spermine metabolism: a palmitoylation-driven pathway to prostate carcinogenesis.

BACKGROUND: Spermine is a natural metabolite that has been shown to hinder the progression of prostate cancer. Protein palmitoylation, a recently identified post-translational lipid modification, is catalyzed by a family of 23 enzymes known as zinc finger DHHC-type palmitoyltransferases (ZDHHCs). This study primarily investigates the role of ZDHHC9 in spermine metabolism and its potential association with prostate cancer. METHODS: We employed immunohistochemistry, Western blotting, and RT-qPCR techniques to assess ZDHHC9 expression in prostate cancer tissues and cell lines. The connection between ZDHHC9 and prostate cancer growth was analyzed using xenograft models, CCK-8 assays, and colony formation experiments. Additionally, we utilized mass spectrometry and RNA sequencing to elucidate how ZDHHC9 modulates spermine metabolism. RESULTS: ZDHHC9 was found to be upregulated and appeared to function as an oncogene in prostate cancer. Both in vitro and in vivo functional experiments confirmed that ZDHHC9 facilitated prostate cancer proliferation and enhanced spermine catabolism in a palmitoylation-dependent manner. Mechanistically, ZDHHC9 interacted with hnRNPU and increased its protein stability through S-palmitoylation at the Cys497 and Cys607 residues. Moreover, the S-palmitoylation of hnRNPU mediated by ZDHHC9 could elevate the expression of SAT1, an enzyme responsible for spermine catabolism, by promoting its transcription. CONCLUSIONS: Our findings establish a new correlation between palmitoylation, spermine metabolism, and prostate carcinogenesis. Targeting the ZDHHC9-hnRNPU-SAT1 signaling axis might provide a novel therapeutic strategy for prostate cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07589-7.