# Unveiling Enhancer RNAs in Gliomas: A Systematic Review and Qualitative Synthesis

## TL;DR

This paper reviews how enhancer RNAs (eRNAs) influence glioma tumor growth, treatment resistance, and patient outcomes, suggesting they could be useful biomarkers for diagnosis and personalized therapy.

## Contribution

The study systematically reviews the role of eRNAs in gliomas, highlighting their potential as biomarkers and therapeutic targets.

## Key findings

- TMZR1-eRNA and LINC02454 modulate temozolomide sensitivity via STAT3 and DDR1 signaling.
- eRNAs like CRNDE and HOXDeRNA correlate with tumor aggressiveness and gliomagenesis.
- Certain eRNAs are associated with poor survival, while others correlate with favorable outcomes in low-grade gliomas.

## Abstract

Enhancer RNAs (eRNAs) are long non-coding RNAs that activate specific genes by interacting with enhancer regions. In gliomas, they are increasingly recognized as molecular regulators of tumor growth, treatment resistance, and patient outcomes. This review summarizes current evidence on glioma-associated eRNAs and their clinical implications. Several eRNAs, including TMZR1-eRNA and LINC02454, influence sensitivity to temozolomide (the main chemotherapeutic agent for glioma) by modulating STAT3 and DDR1 signaling. Others, such as HOXDeRNA and CRNDE, correlate with tumor aggressiveness and survival. By linking enhancer activity to tumor behavior, eRNAs represent promising biomarkers for diagnosis, disease monitoring, and personalized therapy development in neuro-oncology.

Background: Enhancer RNAs (eRNAs), a subclass of long non-coding RNAs transcribed from enhancer regions, have emerged as dynamic regulators of gene expression, tumor progression, and therapeutic response. In gliomas, their biological and clinical significance is only recently being elucidated. This systematic review aimed to synthesize current evidence regarding the role of eRNAs in gliomagenesis, chemoresistance, and prognosis. Methods: We conducted a systematic review following PRISMA 2020 guidelines. PubMed/MEDLINE and Scopus databases were searched on September 2025 using a predefined strategy. Eligible studies included clinical or pre-clinical analyses of eRNAs in gliomas, reporting associations with tumorigenicity, survival, or resistance to temozolomide (TMZ). Risk of bias was assessed using ROBINS-I (Version 2), and findings were qualitatively synthesized. Results: From 26 retrieved records, 10 studies were included, encompassing 22 unique eRNAs. Two studies demonstrated that TMZR1-eRNA and LINC02454* modulate TMZ sensitivity by regulating STAT3, SORBS2, and DDR1 pathways. Seven studies evaluated prognostic implications: 12 eRNAs (e.g., AC003092.1, CYP1B1-AS1, CRNDE) were consistently associated with poor survival, while seven (e.g., LINC00844, ENSR00000260547) correlated with favorable outcomes, particularly in low-grade gliomas. One mechanistic study showed that HOXDeRNA directly promotes gliomagenesis by displacing PRC2 repression at key transcription factor promoters and activating oncogenic super-enhancers. Conclusions: eRNAs are not passive transcriptional by-products but active modulators of glioma biology. They influence tumor initiation, therapeutic resistance, and survival outcomes, underscoring their potential as prognostic biomarkers and therapeutic targets. Future research should validate these findings in larger clinical cohorts and explore strategies for eRNA-directed therapies in precision neuro-oncology.