Integrative multi-omics analysis identifies key ubiquitination regulators in prostate cancer

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Ubiquitination is vital in tumor regulation, but its role in prostate cancer (PCa) requires further elucidation.
• Identifying key ubiquitination-related genes (URGs) is crucial for understanding PCa pathogenesis.

Purpose of the Study:

• To identify and validate URGs associated with PCa using integrated multi-omics data.
• To investigate the functional role of identified URGs, particularly TRIM8, in PCa progression.

Main Methods:

• Integrated analysis of single-cell RNA sequencing (scRNA-seq) and genome-wide association study (GWAS) data.
• Utilized differential expression analysis, summary data-based Mendelian randomization (SMR), and trajectory analysis.
• Validated findings through immunohistochemistry (IHC), Western blot (WB), quantitative PCR (qPCR), and in vivo/in vitro functional assays.

Main Results:

• Identified POLI and TRIM8 as key causal genes with protective associations against PCa.
• POLI expression was elevated in high-grade PCa, while TRIM8 expression was higher in low-grade tumors and acted as a tumor suppressor.
• Functional experiments confirmed TRIM8's role in suppressing PCa cell migration, proliferation, and tumor growth.

Conclusions:

• POLI and TRIM8 are significant ubiquitination regulators implicated in PCa development with distinct expression patterns.
• TRIM8 functions as a tumor suppressor in PCa, indicating its potential as a therapeutic target.
• The study suggests potential drug-repurposing strategies, including targeting POLI with selegiline hydrochloride.