Comprehensive analysis of a palmitoylation-related prognostic signature in colorectal cancer: Implications for immune therapy and personalized treatment.

Colorectal cancer (CRC) remains one of the leading causes of cancer-associated mortality worldwide. While immune checkpoint inhibitors have shown promise in treatment, there is a need for reliable biomarkers to predict patient prognosis and guide personalized therapies. Palmitoylation, a post-translational modification, has been implicated in various cancer processes, yet its role in CRC prognosis remains unclear. Transcriptome, survival, somatic mutation and copy number variation data were retrieved from The Cancer Genome Atlas, and the GSE17538 dataset was used for external validation. A palmitoylation-related risk signature was developed using univariate Cox regression, Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses. Patients were stratified into high- and low-risk groups based on the median risk score. Prognostic accuracy was assessed using receiver operating characteristic curves and Kaplan-Meier overall survival (OS) analysis with validation in an independent cohort. Functional enrichment, immune cell infiltration and drug sensitivity analyses were performed to explore underlying mechanisms and therapeutic implications. Subsequently, keratin 8 pseudogene 12 (KRT8P12) overexpression was evaluated in HT29 cells, and knockdown HT29 cell lines were generated using lentivirus. Cell proliferation was assessed using Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, cell migration was evaluated by Transwell assay and cell apoptosis was assessed using Annexin-V/propidium iodide staining. A palmitoylation-related risk signature consisting of six genes (KRT8P12, ZDHHC3, PCOLCE2, MPP2, LARS2 and MMAA) was identified. High-risk patients exhibited significantly worse OS (HR=3.19; P<0.001) compared with low-risk patients. Immune cell infiltration analysis revealed enhanced immune activity in the low-risk group, which was associated with higher expression of immune checkpoint genes. Immunotherapy prediction models indicated that low-risk patients might benefit more from immune checkpoint inhibitors. Drug sensitivity analysis identified distinct drug response profiles between the high- and low-risk groups. Furthermore, in vitro, KRT8P12 promoted tumor cell proliferation and migration while inhibiting apoptosis. In conclusion, the present study confirmed the role of KRT8P12 as a palmitoylation-related gene in regulating CRC. In addition, the palmitoylation-associated risk signature may offer a promising tool for prognostic prediction in CRC and could guide personalized treatment strategies, including immune checkpoint inhibitors and targeted therapies.