Targeting post-translational histone modifying enzymes in glioblastoma

Glioblastoma (GBM) is the most common primary brain tumor in adults, and the most lethal form of glioma, characterized by variable histopathology, aggressiveness and poor clinical outcome and prognosis. GBMs constitute a challenge for oncologists because of their molecular heterogeneity, extensive i...

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Published in:Pharmacology & therapeutics (Oxford) 2021-04, Vol.220, p.107721-107721, Article 107721
Main Authors: Kunadis, Elena, Lakiotaki, Eleftheria, Korkolopoulou, Penelope, Piperi, Christina
Format: Article
Language:English
Subjects:
Epigenetic therapy
Glioblastoma
Glioblastoma - drug therapy
Glioblastoma - genetics
Glioblastoma therapy
Glioma
Histone modifications
Histone target therapy
Histones - metabolism
Humans
Neoplasm Recurrence, Local
Protein Processing, Post-Translational
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Summary:Glioblastoma (GBM) is the most common primary brain tumor in adults, and the most lethal form of glioma, characterized by variable histopathology, aggressiveness and poor clinical outcome and prognosis. GBMs constitute a challenge for oncologists because of their molecular heterogeneity, extensive invasion, and tendency to relapse. Glioma cells demonstrate a variety of deregulated genomic pathways and extensive interplay with epigenetic alterations. Epigenetic modifications have emerged as essential players in GBM research, with biomarker potential for tumor classification and prognosis and for drug targeting. Histone posttranslational modifications (PTMs) are crucial regulators of chromatin architecture and gene expression, playing a pivotal role in malignant transformation, tumor development and progression. Alteration in the expression of genes coding for lysine and arginine methyltransferases (G9a, SUV39H1 and SETDB1) and acetyltransferases and deacetylases (KAT6A, SIRT2, SIRT7, HDAC4, 6, 9) contribute to GBM pathogenesis. In addition, proteins of the sumoylation pathway are upregulated in GBM cell lines, including E1 (SAE1), E2 (Ubc9) components, and a SUMO-specific protease (SENP1). Preclinical and clinical studies are currently in progress targeting epigenetic enzymes in gliomas, including a new generation of histone deacetylase (HDAC), protein arginine methyltransferase (PRMT) and bromodomain (BRD) inhibitors. Herein, we provide an update on recent advances in glioma epigenetic research, focusing on the role of histone modifications and the use of epigenetic therapy as a valid treatment option for glioblastoma.
ISSN:0163-7258
1879-016X
DOI:10.1016/j.pharmthera.2020.107721