A Molecular Signature of the Ubiquitin-Proteasome System for Forecasting Prognosis in Thyroid Carcinoma Patients

Background: The ubiquitin-proteasome system (UPS) is vital for protein quality control and its dysregulation is linked to diseases, including cancer. Targeting the UPS is becoming a promising approach in cancer therapy. However, the role of UPS modulation in thyroid carcinoma (THCA) remains to be fully elucidated. Methods: Initially, we utilized data from The Cancer Genome Atlas (TCGA) database to employ weighted gene co-expression network analysis (WGCNA) with LASSO regression to develop a prognostic model for core UPS genes implicated in THCA. Subsequently, we stratified the THCA training set into two distinct subtypes based on ubiquitin-proteasome system prognostic model score (UPS-PMS) characteristics. Key genes within the model were then subjected to functional analysis, immunotherapy evaluation, and drug sensitivity studies. Results: We delineated a prognostic model of the UPS comprising six genes, which we subsequently demonstrated was capable of forecasting patient prognosis. Moreover, our findings indicated a substantial correlation between UPS-PMS and immune microenvironmental factors, notably a negative correlation with myeloid immune cells and a potential influence on the Th1 to Th2 cells ratio. Especially, we observed a significant association between high UPS-PMS and an immunosuppressive microenvironment. Then, we elucidated the biological distinctions among various THCA sample subtypes, highlighting that the cluster_1 subtype is associated with an unfavorable prognosis. Of note, KCNA1 was identified as a pivotal prognostic gene within the UPS-PMS framework. We constructed a three-tiered regulatory network centered on KCNA1-related competing endogenous RNA (ceRNA). Furthermore, our results suggested that KCNA1 has potential as a target for immunotherapeutic strategies. Concurrently, drug sensitivity analyses demonstrated that high KCNA1 expression promoted gemcitabine resistance in patients, while KCNA1 knockdown increased sensitivity to gemcitabine. Conclusion: In conclusion, we developed a novel UPS-based prognostic model for THCA, identified key gene KCNA1, and assessed immunotherapy and drug sensitivity, revealing new therapeutic targets. Keywords: ubiquitin-proteasome system, thyroid carcinoma, prognostic model, immune microenvironment, drug sensitivity