• Identified 31 PTM-related genes enriched in deubiquitination and histone modification pathways in endometrial cancer. • Integrated LASSO, SVM, and Random Forest to define a robust six-gene signature (KAT2B, MYC, PDGFRB, PSMD14, RNFT2, UBE2C). • SHAP interpretation revealed UBE2C as the dominant contributor with near-perfect diagnostic performance (AUC ≈ 1). • Single-cell analysis showed PTM activity enriched in proliferative fibroblasts and epithelial cells, linking stromal activation to tumor progression. • Molecular subtypes defined by the six-gene panel exhibited distinct immune infiltration and metabolic reprogramming features. • Mendelian randomization and functional assays consistently demonstrated MYC as a causal driver promoting proliferation, EMT, and apoptosis resistance. Endometrial cancer, the most common gynecological malignancy, represents about 5 % of all cancers in women, with rising incidence rates. Early-stage patients have favorable outcomes, but advanced or recurrent disease leads to poor prognosis and low survival. Current treatments primarily rely on surgery, underscoring the need for new therapeutic targets and biomarkers. Post-translational modifications are crucial in tumor development by regulating protein activity and stability, yet their role in endometrial cancer remains underexplored. We integrated TCGA and GEO endometrial cancer data. PTM scores were calculated using AddModuleScore, and functional enrichment was conducted with clusterProfiler. Single-cell analysis was done with Seurat and Harmony, followed by UMAP and Louvain clustering. Machine learning techniques, including LASSO regression, SVM, and random forest, were applied to identify key genes. SHAP analysis evaluated their diagnostic contributions, and immune cell infiltration was analyzed using ssGSEA. MR on the FinnGen dataset assessed causal links between eQTLs of six genes and endometrial cancer. Differential expression analysis identified 2329 downregulated and 2910 upregulated genes in TCGA, and 2274 downregulated and 2545 upregulated genes in GEO. PTM analysis revealed key pathways, including protein deubiquitination and histone modification. Single-cell analysis identified 12 subpopulations. Six key genes were identified with high diagnostic accuracy. SHAP analysis highlighted UBE2C. MR analysis suggested high MYC expression as a risk factor (OR: 1.67, 95 % CI: 1.07–2.60, P = 0.024). This study provides valuable insights into the role of PTMs in endometrial cancer, identifying potential biomarkers for diagnosis and treatment.
Xiaoming Zhou (Sat,) studied this question.