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bioRxiv · 10.1101/2025.08.30.673297

The Ubiquitin-Proteasome System is an Important Driver of EBV-Associated Nasopharyngeal Carcinoma Progression: A Meta-Analysis of Transcriptomics Data

Ratnawati, H.·Sanjaya, A.·Christiandy, A.·Young, L. S.·Ott, S.
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Abstract

BackgroundEpstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is characterized by extensive immune infiltration, yet immune evasion remains a hallmark of the disease. In this study, we aimed to leverage publicly available datasets to identify EBV-host gene interactions and re-map their expression at single-cell resolution. MethodsWe conducted a meta-analysis of transcriptomic datasets to identify differentially expressed genes in NPC, mapped these genes to EBV-host interaction data, and constructed a network. Network clustering and pathway enrichment were performed, and single-cell RNA sequencing datasets were used to map these genes at cellular resolution. We analysed differences in cell cycle, immune signaling, cell-cell interactions, and assessed prognostic associations of a 12-gene UPS signature using the GEPIA2 platform. ResultsWe identified 85 EBV-interacting DEGs, most regulated by lytic-phase proteins. MCODE clustering highlighted genes related to the ubiquitin-proteasome system (UPS). Single-cell analyses confirmed elevated UPS-related gene expression in NPC compared to EBV-negative oropharyngeal cancer. UPS-High cells exhibited lower proliferative activity, enriched stemness signaling, and reduced antigen presentation and immune activation, whereas UPS-Low cells showed marked upregulation of growth-promoting pathways. Survival analysis revealed that high UPS expression was associated with poorer outcomes in both pan-cancer and head and neck squamous cell carcinoma datasets. The proportion of UPS-High cells varied widely across patients. ConclusionUPS activity, influenced by EBV lytic proteins, is linked to immune evasion, stemness, proliferation, and adverse prognosis. These findings support UPS as a potential biomarker and therapeutic target in EBV-associated NPC, warranting NPC-specific validation and functional studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/673297v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@14032bborg.highwire.dtl.DTLVardef@1c2b995org.highwire.dtl.DTLVardef@126185eorg.highwire.dtl.DTLVardef@9c5f6_HPS_FORMAT_FIGEXP M_FIG C_FIG EBV-driven ubiquitin-proteasome dysregulation in nasopharyngeal carcinoma revealed by bulk and single-cell transcriptomics, linked to immune evasion and poor survival.

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Ratnawati, H., Sanjaya, A., Christiandy, A., Young, L. S., Ott, S.. 2025-09-03. The Ubiquitin-Proteasome System is an Important Driver of EBV-Associated Nasopharyngeal Carcinoma Progression: A Meta-Analysis of Transcriptomics Data. https://doi.org/10.1101/2025.08.30.673297

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