EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma
Bibliographic record
Abstract
BACKGROUND: Enhancer of zeste homolog 2 (EZH2), well known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied noncanonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical su(var)3-9, enhancer-of-zeste and trithorax domain show limited efficacy and lack durable response, suggesting that underlying differences in the noncanonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically distinct, reactive oxygen species (ROS)-stratified tumors. METHODS: We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts. RESULTS: In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of noncanonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, Polycomb Repressive Complex 2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its nonmethyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice. CONCLUSIONS: Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its noncanonical activities and underscoring the significance of patient stratification methodologies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".