Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor, having a poor prognosis and a median overall survival of less than two years. Over the last decade, numerous findings regarding the distinct molecular and genetic profiles of GBM have led to the emergence of several therapeutic approaches. Unfortunately, none of them has proven to be effective against GBM progression and recurrence. Epigenetic mechanisms underlying GBM tumor biology, including histone modifications, DNA methylation, and chromatin architecture, have become an attractive target for novel drug discovery strategies. Alterations on chromatin insulator elements (IEs) might lead to aberrant chromatin remodeling via DNA loop formation, causing oncogene reactivation in several types of cancer, including GBM. Importantly, it is shown that mutations affecting the isocitrate dehydrogenase (IDH) 1 and 2 genes, one of the most frequent genetic alterations in gliomas, lead to genome-wide DNA hypermethylation and the consequent IE dysfunction. The relevance of IEs has also been observed in a small population of cancer stem cells known as glioma stem cells (GSCs), which are thought to participate in GBM tumor initiation and drug resistance. Recent studies revealed that epigenomic alterations, specifically chromatin insulation and DNA loop formation, play a crucial role in establishing and maintaining the GSC transcriptional program. This review focuses on the relevance of IEs in GBM biology and their implementation as a potential theranostic target to stratify GBM patients and develop novel therapeutic approaches. We will also discuss the state-of-the-art emerging technologies using big data analysis and how they will settle the bases on future diagnosis and treatment strategies in GBM patients.
Highlights
Glioblastoma (GBM) is the most aggressive type of primary brain tumor
Aberrant insulator function could be associated with missense mutations in the CCCTC-binding factor (CTCF) coding region and CTCF binding sites (CBSs), leading to disrupted loop-formation activity and gene expression dysregulation [27–29]
Differentiation of embryonic stem cells (ESCs) into neural precursors has been correlated with a gain of structural loops and enhanced binding of CTCF and cohesin leading to durable insulation between chromatin boundaries, limiting the enhancer– promoter interaction to the detriment of the activation of developmental genes [52]
Summary
Glioblastoma (GBM) is the most aggressive type of primary brain tumor. The current standard-of-care (SOC) for patients with GBM includes a combination of surgical resection, adjuvant radiotherapy, and chemotherapy, mainly based on temozolomide (TMZ) [1, 2]. Genetic and epigenetic alterations on insulator elements (IEs), an essential type of cis-regulatory element involved in enhancer–promoter interactions, have been recently found in cancer cells [10]. It provides an overview of the chromatin architecture and IEs in glioma stem cells (GSCs) and its potential translation into novel patient-centered diagnosis, prognosis, and therapeutic applications.
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