Downregulation of the Ubiquitin-E3 Ligase RNF123 Promotes Upregulation of the NF-κB1 Target SerpinE1 in Aggressive Glioblastoma Tumors

Abstract

This study investigated the functional significance of the ubiquitin E3-ligase RNF123 in regulating downstream targets of the NF-κB1 signaling pathway and its impact on glioblastoma (GB) progression, particularly in patients with wild-type isocitrate dehydrogenase 1 and 2 (IDH WT). Through a combination of molecular and clinical analyses, we identified a novel oncogenic signaling cascade involving miR-155-5p, RNF123, NF-κB1 p50, and SerpinE1, which may offer new therapeutic opportunities for this aggressive form of brain cancer.

Mechanistically, we found that RNF123 expression is significantly reduced in IDH WT GB patients. This downregulation leads to decreased levels of p50, a key component of the NF-κB1 complex. RNA-sequencing and reverse-phase protein array analyses, combined with functional assays conducted in IDH WT GB cell lines engineered to overexpress RNF123, identified SerpinE1 as a downstream effector that is negatively regulated by RNF123. Functional knockdown of SerpinE1 in these cells significantly reduced both proliferation and invasion, supporting its role as a mediator of tumor aggressiveness.

Furthermore, both SerpinE1 and miR-155-5p were shown to suppress RNF123 expression, suggesting the existence of a feedback loop that reinforces oncogenic signaling. Translational clinical analysis revealed that elevated expression of miR-155-5p and SerpinE1, along with reduced RNF123, were each associated with poor clinical outcomes in glioblastoma patients. In multivariable survival analysis focused on the IDH WT patient subgroup, the combination of low RNF123 and high SerpinE1 expression emerged as an independent prognostic indicator. This expression profile was strongly correlated with significantly reduced overall survival (p < 0.001; hazard ratio = 2.93; 95% CI: 1.7–5.05) and an increased likelihood of tumor recurrence (p < 0.001; relative risk = 3.56; 95% CI: 1.61–7.83).

In summary, our findings reveal that RNF123 acts as a tumor suppressor in glioblastoma by modulating NF-κB1 signaling through its regulation of p50 and SerpinE1. The identified miR-155-5p–RNF123–NF-κB1–SerpinE1 axis provides new insights into glioblastoma biology and may serve as a promising target for therapeutic intervention, particularly in patients with IDH WT GB CC-885.

Keywords: KPC1; NF-κB pathway; PAI-1; miR-155; p50.

Conflict of Interest Statement

G.B.M. discloses advisory or consulting roles with AstraZeneca, Chrysallis Biotechnology, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, and Zentalis. Financial interests include stock or options in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. Intellectual property includes licensed technology for an HRD assay to Myriad Genetics and DSP patents with Nanostring. Sponsored research was conducted with Nanostring Center of Excellence and Ionis (provision of tool compounds).