Palmitoylation-related gene expression and its prognostic value in prostate cancer: insights into immune infiltration and therapeutic potential

Prostate cancer (PRAD/PCa) is a leading malignancy in men, with high incidence and mortality rates globally. Although treatments like androgen deprivation therapy (ADT) and chemotherapy have advanced, the prognosis for advanced or metastatic PCa remains unfavorable. Post-translational modifications (PTMs), particularly protein palmitoylation, have emerged as critical regulators of cancer progression and potential therapeutic targets. This study investigates the features of palmitoylation-related genes (PRGs) in PRAD, their links to immune infiltration, and potential therapeutic applications.

RNA-seq data and clinical information for PRAD were sourced from The Cancer Genome Atlas (TCGA), Deutsches Krebsforschungszentrum (DKFZ), Memorial Sloan Kettering Cancer Center (MSKCC), Gene Expression Omnibus (GEO), ArrayExpress, PCaProfiler, and PCaDB. Palmitoylation scores were calculated using the single-sample gene set enrichment analysis (ssGSEA) method. A prognostic model was developed based on characteristic genes from single-cell RNA sequencing (scRNA-seq) and validated in multiple external datasets. An integrative machine learning approach combining ten algorithms was used to construct a PRG signature. Potential drug sensitivity was analyzed using the oncoPredict R package, and experimental validation was performed on human prostate samples and PRAD cell lines.

Significant variations in palmitoylation scores were observed across different PRAD patient types and cell populations. Higher palmitoylation scores were associated with poorer biochemical recurrence (BCR)-free survival in the TCGA dataset. The developed prognostic signature demonstrated significant differences in BCR among patients stratified by risk score. Patients with elevated risk scores demonstrated advanced clinical features such as increased age, advanced tumor stage, lymph node metastasis, elevated prostate-specific antigen (PSA) levels, higher Gleason scores, and BCR. Transcriptomic analysis identified unique gene expression profiles and pathway activities between high- and low-risk groups, with the high-risk group exhibiting heightened activation of oncogenic and immune-related pathways. PRG risk scores significantly impacted the immune landscape, with the high-risk group showing elevated immune checkpoint expression [e.g., programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1)] and a more immunosuppressive microenvironment. Drug response analysis indicated that patients with different risk scores may respond differently to chemotherapy, with significant differences in the half-maximal inhibitory concentration (IC50) values for common chemotherapeutic agents. Functional importance and validation of hub genes, including cholinergic receptor nicotinic alpha 2 subunit (CHRNA2), supported their potential as therapeutic targets. Experimental validation of CHRNA2 knockdown in PRAD cells demonstrated significant inhibition of cell growth, migration, and invasion.

This study underscores the prognostic importance of PRG expression in PRAD, linking it to tumor biology, immune infiltration, and treatment response. Targeting palmitoylation pathways may offer novel therapeutic opportunities for improving patient outcomes in PRAD. Future research should aim to clarify the molecular mechanisms of palmitoylation in PRAD and investigate its therapeutic potential through preclinical and clinical studies.