Ubiquitination-anchored signature defines neuroendocrine prostate cancer: hub genes and single-cell ecosystem insights from integrated bioinformatics analysis of public transcriptomic datasets.

BACKGROUND

Neuroendocrine prostate cancer (NEPC) is an aggressive, treatment-refractory state that often emerges under androgen-receptor pathway inhibition. We hypothesized that dysregulated ubiquitination underpins NEPC lineage plasticity and that integrating bulk and single-cell transcriptomes would define a ubiquitination-centered signature and tumor microenvironment (TME) circuits of diagnostic and therapeutic relevance.

METHODS

Public bulk transcriptomic datasets were combined to compare NEPC with prostate adenocarcinoma, including a GEO discovery cohort of 49 tissue samples from GSE32967 and GSE104786, and intersected with a curated ubiquitination-related gene universe to derive ubiquitination-related differentially expressed genes (URDEGs). Co-expression networks, functional enrichment, and protein-protein interaction (PPI) network topology analyses were used to identify and prioritize candidate hub genes. An independent scRNA-seq cohort was integrated for biological contextualization to map cellular lineages, hub gene localization, and intercellular communication.

RESULTS

We identified 317 URDEGs that clearly segregated NEPC from conventional prostate cancer and clustered into NEPC-associated modules enriched for cell-cycle and mitotic programs. Network integration yielded an 11-gene hub panel, including AURKA, CCNA2, EZH2, FGFR1, and TTK. In the single-cell dataset, 25,325 cells were retained after quality control, and UMAP resolved 17 clusters annotated into 8 major lineages. Single-cell mapping further revealed lineage-biased hub gene expression and highlighted a prominent stromal-vascular as well as immune MIF-CD74/CXCR4 signaling axis.

CONCLUSIONS

This integrative analysis identifies a ubiquitination‑anchored transcriptomic signature and associated hub‑gene network that are consistently associated with NEPC in public bulk datasets and supported by cell‑type-resolved patterns in an independent scRNA‑seq cohort; these findings nominate candidate biomarkers and therapeutic hypotheses that warrant external validation in prospectively collected, clinically annotated cohorts with protein‑level assessment.