Multi-omics analysis and functional validation reveal the oncogenic role of TRIP13

Thyroid hormone receptor-interacting protein 13 (TRIP13), an enzyme from the AAA-ATPase family, facilitates the assembly or disassembly of protein complexes and participates in various biological processes. However, its impact on cancer immune infiltration and pan-cancer prognosis remains largely unexplored.

Pan-cancer multi-omics data from publicly available resources were systematically analyzed to evaluate TRIP13 expression across various cancer types and its association with patient prognosis. In addition, functional enrichment analyses were conducted to investigate TRIP13-related biological processes and pathways. The analysis included GSEA enrichment, correlation with immune regulator expression, tumor immune cell infiltration, association with tumor mutational burden (TMB), and correlation with microsatellite instability (MSI). Additionally, single-cell data were used to explore the expression and potential role of TRIP13 at the single-cell level. We subsequently conducted a series of in vitro experiments.

Our comprehensive pan-cancer analysis reveals significantly elevated TRIP13 expression across multiple cancer types and links it to poor prognostic outcomes. TRIP13 primarily activates pathways such as ubiquitination, cell cycle regulation, and DNA repair to drive tumor progression. Additionally, TRIP13 expression exhibits complex associations with various immune regulators and immune cells. In prostate cancer, TRIP13 shows marked overexpression and is associated with unfavorable prognosis. We identified a significant upregulation of TRIP13 in proliferative tumor stem-like populations in prostate cancer. Consistently, prostate cancer cells that acquired resistance to CDK4/6 inhibitors displayed marked TRIP13 overexpression, and functional assays revealed that TRIP13 modulates cellular sensitivity to these agents. Mechanistically, we demonstrated that E2F1 transcriptionally activates TRIP13, which in turn drives the upregulation of the downstream ubiquitin ligase HECTD3.

This study reveals aberrant TRIP13 expression across multiple cancers and its association with immune modulation and tumor aggressiveness. The elevation of TRIP13 in palbociclib resistant prostate cancer, together with the regulatory E2F1-TRIP13-HECTD3 axis, highlights its potential as a prognostic biomarker and therapeutic target.