Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. Transcription factors (TFs) are master regulators of gene expression programs, which ultimately shape cell fate and homeostasis. A variety of TFs have been detected to be aberrantly expressed in brain tumors, being highly implicated in critical pathological aspects and progression of gliomas. Herein, we describe a selection of oncogenic (GLI-1/2/3, E2F1–8, STAT3, and HIF-1/2) and tumor suppressor (NFI-A/B, TBXT, MYT1, and MYT1L) TFs that are deregulated in gliomas and are subsequently associated with tumor development, progression, and migratory potential. We further discuss the current targeting options against these TFs, including chemical (Bortezomib) and natural (Plumbagin) compounds, small molecules, and inhibitors, and address their potential implications in glioma therapy.

Non-coding segments of the human genome are enriched in cis-regulatory modules that constitute functional elements, such as transcriptional enhancers and Super-enhancers. A hallmark of cancer pathogenesis is the dramatic dysregulation of the “archetype” gene expression profiles of normal human cells. Genomic variations can promote such deficiencies when occurring across enhancers and Super-enhancers, since they affect their mechanistic principles, their functional capacity and specificity, and the epigenomic features of the chromatin microenvironment across which these regulatory elements reside. Here, we comprehensively describe: fundamental mechanisms of gene expression dysregulation in cancers that involve genomic abnormalities within enhancers’ and Super-enhancers’ (SEs) sequences, which alter the expression of oncogenic transcription factors (TFs); cutting-edge technologies applied for the analysis of variation-enriched hotspots of the cancer genome; and pharmacological approaches for the treatment of Super-enhancers’ aberrant function. Finally, we provide an intratumor meta-analysis, which highlights that genomic variations in transcription-factor-driven tumors are accompanied overexpression of genes, a portion of which encodes for additional cancer-related transcription factors.

Cancer is a disease caused by (epi)genomic and gene expression abnormalities and characterized by metabolic phenotypes that are substantially different from the normal phenotypes of the tissues of origin. Metabolic reprogramming is one of the key features of tumors, including those established in the human nervous system. In this work, we emphasize a well-known cancerous genomic alteration: the amplification of MYCN and its downstream effects in neuroblastoma phenotype evolution. Herein, we extend our previous computational biology investigations by conducting an integrative workflow applied to published genomics datasets and comprehensively assess the impact of MYCN amplification in the upregulation of metabolism-related transcription factor (TF)-encoding genes in neuroblastoma cells. The results obtained first emphasized overexpressed TFs, and subsequently those committed in metabolic cellular processes, as validated by gene ontology analyses (GOs) and literature curation. Several genes encoding for those TFs were investigated at the mechanistic and regulatory levels by conducting further omics-based computational biology assessments applied on published ChIP-seq datasets retrieved from MYCN-amplified- and MYCN-enforced-overexpression within in vivo systems of study. Hence, we approached the mechanistic interrelationship between amplified MYCN and overexpression of metabolism-related TFs in neuroblastoma and showed that many are direct targets of MYCN in an amplification-inducible fashion. These results illuminate how MYCN executes its regulatory underpinnings on metabolic processes in neuroblastoma.

Gliomas encompass a vast category of CNS tumors affecting both adults and children. Treatment and diagnosis are often impeded due to intratumor heterogeneity and the aggressive nature of the more malignant forms. It is therefore essential to elucidate the molecular mechanisms and explore the intracellular signaling pathways underlying tumor pathology to provide more promising diagnostic, prognostic, and therapeutic tools for gliomas. The tripartite motif-containing (TRIM) superfamily of proteins plays a key role in many physiological cellular processes, including brain development and function. Emerging evidence supports the association of TRIMs with a wide variety of cancers, exhibiting both an oncogenic as well as a tumor suppressive role depending on cancer type. In this review, we provide evidence of the pivotal role of TRIM proteins in gliomagenesis and exploit their potential as prognostic biomarkers and therapeutic targets.

Central nervous system (CNS) tumors consist of a diverse set of malignancies that remain clinically challenging due to their biological complexity, high morbidity, and limited responsiveness to current therapies. A growing body of genomic evidence has revealed that dysregulation of the mitogen-activated protein kinase (MAPK) signaling pathway is a recurrent and unifying characteristic across many pediatric and adult CNS tumor entities. Alterations affecting upstream receptor tyrosine kinases (RTKs), RAS GTPases, RAF kinases, and other associated regulators contribute to MAPK signaling pathway hyperactivation, shaping tumor behavior, therapy response and resistance. These aberrations ranging from hotspot mutations such as BRAF V600E and oncogenic fusions like BRAF–KIAA1549 are particularly enriched in gliomas and glioneuronal tumors, highlighting MAPK signaling as a key oncogenic driver. The expanding availability of molecularly targeted compounds, including selective inhibitors of RAF, MEK and ERK, has begun to transform treatment approaches for specific molecular subtypes. However, the clinical benefit of MAPK-directed therapies is frequently limited by restricted blood–brain barrier (BBB) penetration, intratumoral heterogeneity, parallel pathway reactivation, and an immunosuppressive tumor microenvironment (TME). In this review, we synthesize current knowledge on MAPK pathway alterations in CNS tumors and evaluate the therapeutic landscape of MAPK inhibition, with emphasis on approved agents, emerging compounds, combination strategies, and novel drug-delivery technologies. We also discuss mechanisms that undermine treatment efficacy and highlight future directions aimed at integrating MAPK-targeted therapy into precision-based management of brain tumors.