Targeting ADAR stability: a novel approach to combat glioblastoma

Adenine deaminase (ADAR) is a key RNA editing enzyme that plays an important role in the initiation and progression of cancer. However, the mechanisms regulating its protein stability and its function in glioblastoma (GBM) remain unclear.

This study systematically investigated the expression patterns of ADAR across pan-cancer types and its specific mechanisms in GBM through the integration of multi-omics data analysis and experimental validation. We performed bioinformatics analysis on the TCGA dataset, utilising single-cell RNA sequencing data, in vitro functional experiments, and molecular studies including co-immunoprecipitation and ubiquitination detection.

We found that ADAR exhibits significant differential expression across various cancers and is closely associated with tumour mutation burden and survival outcomes. Further analysis revealed that ADAR is highly expressed in GBM and primarily enriched in tumour cells, with its expression levels significantly positively correlated with key cancer signalling pathways such as PI3K-AKT-mTOR and G2M checkpoints. Functional experiments confirmed that ADAR significantly promotes the migratory capacity of glioblastoma cells. Importantly, we identified E3 ubiquitin ligase STUB1 as a specific regulator of ADAR, which mediates ADAR's proteasome-dependent degradation by promoting K48-linked ubiquitination of ADAR. Knocking down STUB1 significantly upregulates ADAR protein levels and enhances tumour cell migration capacity.

This newly identified STUB1-ADAR regulatory axis not only elucidates the molecular mechanisms underlying ADAR homeostasis but also provides new potential strategies for targeted therapy against glioblastoma.