SUMOylation and palmitoylation in metastatic prostate cancer: A compartment-based framework for nuclear and membrane adaptation.

Metastatic prostate cancer remains lethal despite treatment intensification, in part because tumor cells can adopt rapid and reversible states that are not fully explained by genomic alterations. Post-translational modifications provide a dynamic regulatory layer by changing protein activity, localization, stability, and molecular interactions. This Review evaluates SUMOylation and reversible S-palmitoylation as compartment-biased systems that regulate complementary dimensions of metastatic adaptation. SUMOylation has a comparatively mature mechanistic foundation in androgen receptor transcription, chromatin organization, DNA damage responses, tumor-suppressor function, and stress adaptation. The prostate cancer palmitoylation literature is smaller, but it identifies discrete mechanisms involving androgen-regulated protein acylation, receptor and cytoskeletal signaling, lipid metabolism, ferroptosis, and immune regulation. We propose that these modifications converge functionally at pathway and cell-state levels rather than forming an established biochemical circuit. Their shared outputs may include treatment persistence, metabolic adaptation, cellular plasticity, invasion, and tumor-microenvironment interactions. Translation should therefore prioritize disease-specific enzyme-substrate dependencies, direct measures of target engagement, and mechanistically matched combinations with established therapies rather than global or simultaneous inhibition of both modification systems.