What Epigenetics Teaches Us About Neuron-Glioma Interactions.

Neuron-glioma interactions are critical drivers of glioma progression, with neuronal activity promoting tumor growth and invasion through paracrine signaling and direct synaptic input. Beyond well-established glutamatergic synapses, recent discoveries revealed that GABAergic interactions also contribute to glioma proliferation. Here, we focus on how glioma cells decode neuronal cues via epigenetic mechanisms, including enhancer reprogramming, chromatin remodeling, and rewiring of 3D genome organization, with transcriptions factors such as SMAD3 and PITX1 orchestrating transcriptional programs that sustain neuron-to-glioma communication. Additionally, recent integration of multi-omics data highlights gene regulatory networks linked to GABAergic signaling as contributors to glioblastoma (GB) pathogenesis. We also underscore the distinct roles of GABAergic signaling across glioma subtypes, noting that, in GB, GABA-related metabolic and paracrine mechanisms, rather than synaptic input, may drive tumor progression. Understanding how epigenetic reprogramming facilitates glioma integration into neural circuits opens new avenues to disrupt these malignant neuron-glioma interactions by targeting the epigenetic machinery.