Abstract
Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.
Highlights
Gliomas account for the majority of primary central nervous system (CNS) neoplasms, encompassing a diverse set of tumors, commonly of highly aggressive phenotype with limited therapeutic options [1]
We focus on the effect of histone post-translational modifications (PTMs) and bivalent genes in gliomas heterogeneity and plasticity, addressing potential therapeutic targeting options
In this context of plasticity, bivalent gene regulation of developmental genes allows for the expression of stem cell genes, such as those of the HOX family
Summary
Gliomas account for the majority of primary central nervous system (CNS) neoplasms, encompassing a diverse set of tumors, commonly of highly aggressive phenotype with limited therapeutic options [1]. These findings could further favor research within subgroups in order to select specific treatments for each tumor type and improve the design of future clinical trials Some of these mutations, like IDH and H3K27M attract epigenetic enzymes and induce epigenetic changes in gliomas, mainly DNA hypermethylation and repressive histone modifications (H3K27me3) that can further control gene expression in a reversible and specific way [8,9,10]. DNA methylation is the most studied mechanism of gene silencing occurring mainly in CpG islands of gene promoters, having been implicated in several diseases, including cancer Another level of gene regulation is conferred by the post-translational modifications (PTMs) taking place on histone N-terminal tails, charged with arginine and lysine residues and include methylation, acetylation, phosphorylation, and ubiquitination [12]. We focus on the effect of histone PTMs and bivalent genes in gliomas heterogeneity and plasticity, addressing potential therapeutic targeting options
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