Ubiquitin-proteasome Pathway-linked Gene Signatures as Prognostic Indicators in Prostate Cancer.

Abstract

Background/aim: Prostate cancer (PCa) is the most frequently diagnosed cancer in men and a leading cause of cancer-related death. While prostate-specific antigen is a widely used biomarker, its specificity is limited. This study investigated the prognostic significance of gene subsets associated with the ubiquitin-proteasome pathway in PCa.

Materials and methods: We analyzed transcriptomic and clinical data of 94 early-onset (age <55) patients with prostate cancer using public dataset. Differentially expressed genes linked to the ubiquitin-proteasome system were identified across cancer progression stages. Kaplan-Meier survival analysis, Cox regression, and least absolute shrinkage and selection operator (LASSO) modeling were applied to assess their prognostic potential.

Results: Differential expression of IKBKB, UBQLN3, TMUB2, UBE2S, and BRCA1 was observed at relative-early stages of pT3a and Gleason 3+4. Similarly, HERPUD1, CDC20, UHRF1, PSMD7, PIAS3, MALT1, TNF, UBD, CD3E, CD247, SOCS1, UBE2C, CARD16, ZAP70, UBA7, and UBE3C expression levels also changed at pT3b and Gleason 4+3. At metastatic stages (pT4 and Gleason ≥8) OASL expression was up-regulated, whereas that of DDB1, RPN1, UBE3B, UBE2H, PPIL2, WWP2, and CDH1 was down-regulated. In addition, higher expression of PSMD2, CDC20, NFKB1, and STIP1 or lower expression of HERPUD2, NEDD4, ANAPC16, LNX1, and HERPUD1 was associated with poor prognoses according to the Kaplan-Meier or receiver operating characteristic analyses for biochemical recurrence-free survival. A LASSO-Cox model identified six gene candidates including LNX1, PSMD2, SUMO4, UBE2C, UBR5, and UHRF1.

Conclusion: The identified gene subset provides novel prognostic insights into PCa progression and survival. These findings highlight potential biomarkers and therapeutic targets within the ubiquitin-proteasome pathway, offering new avenues for personalized treatment strategies.